Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7](=[O:17])[N:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)=[O:28])[CH:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7](=[O:17])[N:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:21]4[CH:22]=[C:23]([C:27]([C:29]5[CH:39]=[C:38]([CH3:40])[C:32]6[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)=[O:28])[N:24]=[CH:25][N:26]=4)[CH2:13][CH2:12]3)[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: O=C1Nc2ccc(Cl)cc2CCN1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(C(=O)c2cc(N3CCC(N4CCc5cc(Cl)ccc5NC4=O)CC3)ncn2)cc2oc(=O)n(C)c12

Procedure:
56 mg (0.20 mmol) 7-chloro-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 61 mg (0.20 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.070 mL (0.40 mmol) DIPEA were stirred overnight in 1.5 mL DMF at RT. The mixture was diluted with 1.5 mL MeOH, suction filtered, washed with DIPE and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:22][S:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][N:29]4[CH2:30][CH2:31][N:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:27][CH2:28]4)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CN3CCN(S(C)(=O)=O)CC3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and 1-methanesulfonyl-piperazine are processed according to the method described in Example 170 to give 6-chloro-2-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.55 (t, J=4.5 Hz, 4H), 3.14 (t, J=4.5 Hz, 4H), 3.30 (s, 3H), 3.72 (s, 2H), 3.80 (s, 3H), 7.36 (dd, J=8.5, 1.9 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 8.06 (t, J=2.0 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 444.1265 [(M+H)+ Calcd for C22H25ClN5: 444.1261].
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:11]([O:12]C(=O)C)[C@:10]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24](=[O:34])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[CH:18]=3)[O:16][C@@:7]([CH2:35][O:36]C(=O)C)([CH2:8][O:9]2)[C@H:6]1[O:40]C(=O)C)(=O)C.[BH4-].[Na+]>CO>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C@@:10]23[O:16][C@@:7]([CH2:35][OH:36])([CH2:8][O:9]2)[C@@H:6]([OH:40])[C@H:5]([OH:4])[C@H:11]3[OH:12])=[CH:18][C:19]=1[CH:24]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH3:33])=[CH:29][CH:30]=1)[OH:34]
Reactant: CCOc1ccc(C(=O)c2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1ccc(C(O)c2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of acetic acid (1R,2S,3S,4R,5S)-3,4-diacetoxy-1-acetoxymethyl-5-[4-chloro-3-(4-ethoxy-benzoyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-2-yl ester (see Example 11 for preparation; 85 mg, 0.14 mmol) in methanol (3 mL) was added sodium borohydride (25 mg, 0.66 mmol) at room temperature. After one hour, the reaction was quenched by the addition of water (20 mL) and the resulting mixture was concentrated under reduced pressure. The resulting aqueous layer was extracted three times with ethyl acetate (15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. To a solution of this crude material in methanol (5 mL) was added sodium methoxide in methanol (25% wt) until pH 12 was obtained and the resulting mixture was stirred at room temperature. After 16 hours, the reaction mixture was neutralized by the addition of Dowex Monosphere 650C (H) cation exchange resin (the resin was washed with methanol 3 times before use) until the pH of the solution was <7. The reaction mixture was filtered and concentrated under reduced pressure. The resulting material was precipitated from ethyl acetate and heptane. The resulting solid was washed with heptane 2 times and dried under reduced pressure to yield the desired product (58.9 mg, 93% yield) as a white solid. MS (LCMS) 497.3 (M+HCOO−, negative mode) 1H NMR (400 MHz, METHANOL-d4) delta ppm 1.33 (t, J=6.9 Hz, 6 H), 3.56 (d, J=8.0 Hz, 1 H), 3.59-3.64 (m, 3 H), 3.64-3.69 (m, 2 H), 3.68 (d, J=12.5 Hz, 2 H), 3.78 (d, J=8.2 Hz, 2 H), 3.84 (d, J=12.5 Hz, 2 H), 3.98 (q, J=7.0 Hz, 4 H), 4.15 (d, J=7.4 Hz, 1 H), 4.16 (d, J=7.4 Hz, 1H), 6.04 (s, 1 H), 6.05 (s, 1 H), 6.80 (d, J=8.4 Hz, 4 H), 7.21 (d, J=8.6 Hz, 2 H), 7.22 (d, J=8.6 Hz, 2 H), 7.29 (d, J=8.2 Hz, 2 H), 7.40-7.42 (m, 2 H), 7.91 (d, J=2.0 Hz, 1 H), 7.93 (d, J=2.0 Hz, 1 H).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:40])[C:15]2[O:21][C:20]3[C:22]([Cl:36])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][NH:29][CH2:30][C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:38])(=[O:37])[C:16]=2[CH:39]=1)=[O:11].[CH:41](=O)[CH3:42].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:40])[C:15]2[O:21][C:20]3[C:22]([Cl:36])=[CH:23][C:24]([N:26]([CH2:2][CH3:3])[CH2:27][CH2:28][N:29]([CH2:41][CH3:42])[CH2:30][C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:38])(=[O:37])[C:16]=2[CH:39]=1)=[O:11]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCc3cccs3)cc(Cl)c1O2
Reactant: CC=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CCN(CC)c1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2)Cc1cccs1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.05 mL, 0.67 mmol) was added to a solution of Example 86k (0.17 g, 0.335 mmol) in methanol (10 mL) at 0° C. Acetaldehyde (1 mL, 19.5 mmol) was added and the reaction mixture was stirred at 0-10° C. for 2 h. The reaction mixture was brought to room temperature, treated with sodium cyanoborohydride (0.092 g, 1.34 mmol) and left stirring overnight. It was treated with an aqueous sodium bicarbonate solution, concentrated, treated with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, 20% ethyl acetate/pet ether) to obtain the title compound. Yield: 0.11 g, (58.3%); 1H NMR (CDCl3): δ 1.1 (q, 6H, 2CH3), 2.62 (t, 4H, 2CH2), 2.65 (s, 3H, CH3), 3.32 (m, 4H, 2CH2), 3.83 (s, 2H, CH2), 3.92 (s, 3H, CH3), 5.2 (s, 2H, CH2), 6.32 (s, 1H, CH2), 6.52 (s, 1H, Ar), 7.00 (m, 2H, Ar), 7.32 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.45 (s, 1H, Ar); MS: m/e (ES+) 563 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]([C:7](=[O:19])[N:8]([CH2:16][CH:17]=C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=C>C(Cl)Cl.[Ru]>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:7](=[O:19])[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:16][CH:17]=1
Reactant: C=CCN(Cc1ccccc1)C(=O)C(=C)CC(=O)OC
Agent: [Ru]
Solvent: ClCCl
Product: COC(=O)CC1=CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 733.9 %

Procedure:
234 mg of 3-(allyl-benzyl-carbamoyl)-but-3-enoic acid methyl ester (o) (0.1 mmol) prepared by the above Step 1 was added to the catalyst solution containing 36 mg of Grubb's (I) catalyst (0.04 mmol) such as ruthenium dissolved in CH2Cl2 under Ar atmosphere. Then the mixture was stirred for 24 hrs at room temperature, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with EtOAc and hexanes (1:2) as an eluant to give 180 mg of (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-acetic acid methyl ester (p) (yield: 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[S:10](=[O:12])(=[O:11])[NH:9][C:8](=[O:13])[CH2:7]1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>C(O)(=O)C>[O:11]=[S:10]1(=[O:12])[NH:9][C:8](=[O:13])[CH2:7][N:6]1[CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:17](=[O:19])[CH3:18])[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(CN2CC(=O)NS2(=O)=O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cccc(CN2CC(=O)NS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of the title compound of Example 6, 5-(3-aminobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (10 mg, 0.041 mmol) in acetic acid (AcOH, 5 mL) is treated with acetic anhydride (85 mg, 0.83 mmol) and stirred at RT for 72 h. The mixture is stirred with water for 2 h, then concentrated to dryness. The crude mixture is purified by LC/MS to afford N-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)phenyl]acetamide: [M−1]−=282.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[OH:13][C:14]1[N:19]=[C:18]([C:20](Cl)=[O:21])[CH:17]=[CH:16][CH:15]=1>>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:20]([C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:13])[N:19]=3)=[O:21])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1cccc(O)n1
Reactant: COc1cccc2sc(N)nc12
Product: COc1cccc2sc(NC(=O)c3cccc(O)n3)nc12
Yield: 5 %

Procedure:
Using 2-Amino-4-methoxybenzothiazole (450 mg, 2.5 mmol) and 6-hydroxypicolinic acid chloride (1.5 g, 10 mmol) the title compound was obtained as a beige powder in 5% yield. MS: m/e=301 (M+).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]([NH2:26])=[O:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[NH2:26][C:24](=[O:25])[CH2:23][O:22][NH:21][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20]
Reactant: NOCC(N)=O
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: NC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.200 g, 0.723 mmol, US 2005/20572 A1) in DCM (6.0 mL) were added 2-(aminooxy) acetamide 53 (0.098 g, 1.086 mmol), 1-hydroxybenzotriazole (0.147 g, 1.086 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.208 g, 1.086 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 54 (0.203 g, 81%) as a white solid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>>[CH2:16]([O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8]
Reactant: BrCCCCCCCOC1CCCCO1
Reactant: C#CCCCCC#C
Product: C#CCCCCC#CCCCCCCCOC1CCCCO1
Yield: 64.9 %

Procedure:
Oct-1,7-diyne (6.3 g, 59.3 mmol) was alkylated with 2-(7-bromoheptyloxy)tetrahydro-2H-pyran (11 g, 39.56 mmol) as described above to give 2-(pentadeca-8,14-diynyloxy)tetrahydro-2H-pyran (7.82 g, 64%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.6; 1H NMR (400 MHz, CDCl3) δ 4.57 (t, J=2.5 Hz, 1H), 3.82-3.87 (m, 1H), 3.70-3.77 (m, 1H), 3.46-3.51 (m, 1H), 3.36-3.42 (m, 1H), 2.14-2.20 (m, 6H), 1.93 (t, J=2.6 Hz, 1H), 1.46-1.72 (m, 20 H)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: Clc1nccc2ccccc12
Product: Cc1ccc2[nH]c(C)c(-c3nccc4ccccc34)c2c1

Procedure:
The sub-title compound was prepared by the method of Example 10 part a, using 2,5-dimethyl indole and 1-chloroisoquinoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2F)(=[O:19])=[O:18])=[CH:13][N:12]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)(=[O:19])=[O:18])=[CH:13][N:12]=1
Reactant: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)nc1)c1ccccc1F
Reactant: CN1CCNCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccccc2S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
2-[(E)-2-(2,4-Difluorophenyl)vinyl]-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 1, 30 mg, 0.08 mmol) and 1-methylpiperazine (22 μL, 0.20 mmol) were combined in acetonitrile (0.5 mL) and heated to 100° C. for 5 minutes in a Smith synthesiser microwave reactor. Further 1-methylpiperazine (44 μL, 0.40 mmol) was added and the reaction heated to 150° C. for 10 minutes, then to 170° C. for 10 minutes. The reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid and brine, dried over MgSO4 and evaporated in vacuo to give the title compound which was dissolved in ethyl acetate and treated with ethereal HCl to give the hydrochloride salt (10 mg, 25%). δH (500 MHz, MeOD) 9.15 (1H, d, J 2.1), 8.30 (1H, dd, J=1.5, 7.9), 8.25 (1H, dd, J=2.3, 8.4 Hz), 7.96 (1H, d, J=16.3 Hz), 7.84-7.76 (3H, m), 7.56 (1H, td, J=1.1, 7.6 Hz), 7.50 (1H, d, J=7.9 Hz), 7.37 (1H, d, J=16.2 Hz), 7.07-7.03 (2H, m), 3.53 (2H, d, J=12.2 Hz), 3.21-3.14 (2H, m), 3.10 (4H, d, J=6.6 Hz), 3.03 (3H, s); m/z (ES+) 456 [MH+].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[N:11]=[C:12]3[C:18]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:17][N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:13]3=[N:14][CH:15]=2)=[N:7][CH:8]=1>C(Cl)Cl.O=[Mn]=O>[C:19]([C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:8][N:7]=3)[N:11]=2)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH:17]=1)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(CO)cn3)nc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cn3)nc12
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
To a 100 ml three necked round bottom flask 1-(2-(5-(hydroxymethyl)pyridin-2-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethylpropan-1-one (0.5 g, 0.00109 mole) was taken in CH2Cl2 (20 ml). MnO2 (1.9 g, 0.0219 mole) was added in one portion at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 15 min. After completion of the reaction, the reaction mixture was filtered through celite bed and washed with CH2Cl2. The filtrate was collected and concentrated to afford crude product which was subjected for the column purification. The crude compound was purified using column purification by eluting the compound with 25-30% ethyl acetate in hexanes to yield 0.33 g of 6-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)nicotinaldehyde.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=1[C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[O:4].[I-].[Na+].[NH3:27]>O1CCCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[NH:5][C:3](=[O:4])[CH2:2][N:27]=1
Reactant: CCOC(=O)c1cc(C(=O)c2ccccc2Cl)c(NC(=O)CCl)s1
Reactant: N
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(s1)NC(=O)CN=C2c1ccccc1Cl
Temperature: -65 °C

Procedure:
Ethyl 5-(2-chloroacetylamino)-4-(2-chlorobenzoyl)thiophene-2-carboxylate (325 g) and sodium iodide (151.3 g) were added to tetrahydrofuran (3500 ml), and the mixture was refluxed under heating for 1.5 hours. The mixture was cooled to -65° C., and ammonia (164 ml) was added. The reaction temperature was raised slowly to room temperature. The solvent was evaporated, and chloroform and water were added. The organic layer was taken out, washed with water and dried over sodium sulfate. The solvent was evaporated. Toluene (7 l) and silica gel (1365 g) were added thereto, and the mixture was refluxed under heating for 1.5 hours. The silica gel was collected by filtration, and a mixed solvent of chloroform-methanol (10:1) was added to elute the obtained product. The solvent was evaporated, and ethyl acetate was added. The resulting crystals were collected by filtration and washed with ethyl acetate to give 70.0 g of ethyl (5-(2-chlorophenyl)-1,2-dihydro-3H-thieno[2,3-e] [1,4]diazepin-2-on-7-yl)-carboxylate.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[O:5])C.C(O)(=O)C.Cl>O>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:10]1[O:9][N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnoc1-c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cnoc1-c1ccc(Cl)cc1Cl
Yield: 91.2 %

Procedure:
Ethyl-5-(2',4'-dichlorophenyl)-4-isoxazolecarboxylate (50.0 g.; 0.17 mol.) was dissolved in 250 ml. of glacial acetic acid. To the mixture was added 250 ml. of hydrochloric acid and the resultant solution was rapidly stirred at 100° C. for 4 hours. The mixture was then allowed to cool and poured into 2 liters of water. The resultant precipitate was collected, dried, and recrystallized from pentane to yield 5-(2',4'-dichlorophenyl)-4-isoxazolecarboxylic acid (40.0 g.; 93.6% yield) having a melting point of 122°-123° C. and the following analysis:
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[C:10]([OH:14])(=[O:13])[CH:11]=[O:12]>CS(C)=O>[CH3:2][O:12][CH2:11][C:10]([OH:14])=[O:13].[CH3:10][NH:3][C:2]1[N:4]=[C:5]([NH2:6])[N:7]=[C:8]([NH2:9])[N:1]=1
Reactant: O=CC(=O)O
Reactant: Nc1nc(N)nc(N)n1
Solvent: CS(C)=O
Product: CNc1nc(N)nc(N)n1
Product: COCC(=O)O

Procedure:
Melamine and glyoxylic acid are dissolved in dimethylsulfoxide and heated to 50°-80° C. for 5-8 hours. The solvent is removed and replaced by methanol. Sulfuric acid is added as a catalyst and the mixture heated to reflux for 5-10 hours, at which the solution is dried with a drying agent, i.e., 3A molecular sieve. The catalyst is neutralized with base and the methanol removed. The remaining mixture is filtered to yield methyl melamine glycolate methyl ether.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([C:19]3[N:24]([CH3:25])[C:23](=[O:26])[CH:22]=[C:21]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][C:28]=4[F:33])[N:20]=3)[CH2:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[F:33][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:27]=1[C:21]1[N:20]=[C:19]([N:15]2[CH2:16][CH2:17][O:18][C@@H:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])=[CH:8][CH:9]=3)[CH2:14]2)[N:24]([CH3:25])[C:23](=[O:26])[CH:22]=1
Reactant: Cn1c(N2CCO[C@@H](c3ccc(N)cc3)C2)nc(-c2ccncc2F)cc1=O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Nc1ccc([C@H]2CN(c3nc(-c4ccncc4F)cc(=O)n3C)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Methyl chloroformate (0.13 g, 1.38 mmol) was added to a solution of 2-((2S)-2-(4-aminophenyl)morpholine-4-yl)-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one obtained in Example 13 (0.35 g, 0.92 mmol) and triethylamine (0.25 g, 2.47 mmol) in tetrahydrofuran (20 ml) and the solution was stirred at room temperature for one hour. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish methyl (4-((2S)-4-(6-(3-fluoropyridin-4-yl)-3-methyl-4-oxo-3H-pyrimidin-2-yl)morpholin-2-yl)phenyl)carbamate (0.17 g, 42%) as white crystals.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N+:19]([O-:21])=[O:20])=[C:6]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:14])[N:9]([C@H:15]([CH3:18])[CH2:16][OH:17])[CH:8]=[CH:7]3)[CH2:3][CH2:2]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1.C(Cl)Cl>>[C:22]([O:17][CH2:16][C@H:15]([N:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]=2[N+:19]([O-:21])=[O:20])[C:10]1=[O:14])[CH3:18])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](CO)n1ccc2c([N+](=O)[O-])c(C3CC3)ccc2c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C3CC3)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-6-cyclopropyl-2-(1-hydroxypropan-2-yl)-5-nitroisoquinolin-1(2H)-one (30 mg, 0.0001 mol), acetic anhydride (0.015 mL, 0.00016 mol), pyridine (0.015 mL, 0.00019 mol) and methylene chloride (4 mL, 0.06 mol), and was stirred at room temperature overnight. The solvent was removed under reduced pressure and the product was taken onto the next step without purification.
Reaction SMILES: N[C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.N([O-])=O.[Na+].[BrH:19]>>[Br:19][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Br
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Agent: O=N[O-]
Agent: [Na+]
Product: Brc1cc2c(cn1)[nH]c1ccccc12

Procedure:
2 g of 3-amino-β-carboline, suspended in 25 ml of 48% hydrobromic acid, are mixed with 6 ml of a 2-molar sodium nitrite solution at 0°-5° C. The mixture is added at 0°-5° C. to a solution of 2.1 g of copper-I-bromide in 20 ml of 24% hydrobromic acid. The reaction mixture is heated briefly in a steam bath and then repeatedly extracted with a mixture consisting of 9 parts of ethyl acetate and one part of ethane. The combined extracts are evaporated, the residue chromatographed (silica gel, methylene chloride/methanol=19:1). The main fraction crystallizes on treatment with ethyl acetate. Yield: 0.5 g of 3-bromo-β-carboline; melting point: 300° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.Br[CH2:27][CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:27][CH2:28][CH2:29][N:30]4[C:34](=[O:35])[C:33]5[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:31]4=[O:40])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Temperature: 60 °C

Procedure:
4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (0.100 g, 0.305 mmol), N-(3-bromopropyl)-phthalimide (0.163 g, 0.609 mmol, 2.0 equiv) and cesium carbonate (0.248 g, 0.761 mmol, 2.50 equiv) are combined in N,N-dimethylformamide (1.0 mL) and the reaction is heated at 60° C. for 48 hours. The reaction is diluted with water (1 mL) and the reaction mixture is partitioned between ethyl acetate (6 mL) and water (5 mL). The organic layer is removed and placed on a 10 g SCX resin column. The resin is washed sequentially with dichloromethane (20 mL) and 4:1 dichloromethane/2 N ammonia in methanol (125 mL). The latter fractions are evaporated to dryness and the residue is subjected to chromatography on silica gel (20 g) (9:1 ethyl acetate: methanol (2 N ammonia)) to yield the desired product as a tan solid, 0.117 g (75%).