Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][C@@H:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=2)=[CH:27][N:26]=1>CN(C)C=O>[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([NH:11][C@@H:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[O:38])=[N:35][CH:36]=2)=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: Nc1ncc(-c2ccc(C(=O)O)nc2)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc(N)nc2)cn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
N,N-Diisopropylethylamine (1.13 mL, 6.48 mmol) was added to a mixture of tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (0.250 g, 1.12 mmol), and 5-(2-aminopyrimidin-5-yl)pyridine-2-carboxylic acid (0.242 g, 1.12 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at RT for 3 h, and filtered. The filtrate was diluted with methanol (10 mL). The resulting solution was purified by RP-HPLC (pH 10) to give the desired product (182 mg, 42.3%). LCMS: (M+H)=386.2.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:13]=[N:14][N:15]([CH:17]4[CH2:20][O:19][CH2:18]4)[CH:16]=3)[CH:8]=2)[N:3]1[C:21](=[O:23])[CH3:22].[CH3:24][CH:25]([CH3:30])[CH2:26][C:27](Cl)=[O:28].N1C=CC=CC=1>ClCCl>[C:21]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:12]3[CH:13]=[N:14][N:15]([CH:17]4[CH2:20][O:19][CH2:18]4)[CH:16]=3)=[CH:6][CH:5]=2)[N:10]([C:27](=[O:28])[CH2:26][CH:25]([CH3:30])[CH3:24])[CH2:11][C@@H:2]1[CH3:1])(=[O:23])[CH3:22]
Reactant: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2NC[C@@H]1C
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)CC(C)C)C[C@@H]1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
A 100-mL round-bottom flask was charged with (S)-1-(2-methyl-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (50 mg, 0.16 mmol), 3-methylbutanoyl chloride (93 mg, 0.77 mmol), pyridine (63 mg, 0.80 mmol, 5.00 equiv) and dichloromethane (30 mL). The resulting solution stirred for 30 min at 0° C. in a water/ice bath and an additional 3 h at room temperature. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 2-50% ethyl acetate-petroleum ether) to afford (S)-1-(4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)-3-methylbutan-1-one (26.7 mg, 42%) of as light yellow oil. 1H NMR (300 MHz, CD3OD) δ ppm 079 (br s, 3 H), 0.93 (d, J=6.60 Hz, 3 H), 1.18 (d, J=6.30 Hz, 3 H), 1.90-2.10 (m, 1 H), 2.42 (s, 3 H), 2.35-2.43 (m, 1 H), 2.48-2.50 (m, 1 H), 2.51-2.89 (m, 1 H), 4.80-4.95 (m, 2 H), 5.08 (d, J=6.90 Hz, 4 H), 5.55-5.65 (m, 1 H), 7.38-7.45 (m, 1 H), 7.55-7.75 (m, 2 H), 8.03 (s, 1 H), 8.24 (s, 1 H). MS (ESI, pos. ion) m/z 425 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[CH:11][CH:12]=2)[N:7]([CH3:19])[CH:6]=1.[NH4+:21].[OH-]>C(Cl)Cl>[N:14]1([C:10]2[CH:9]=[C:8]3[C:13]([C:5]([CH2:4][C:3]([NH2:21])=[O:2])=[CH:6][N:7]3[CH3:19])=[CH:12][CH:11]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: [NH4+]
Reactant: COC(=O)Cc1cn(C)c2cc(-n3ccnc3)ccc12
Agent: [OH-]
Solvent: ClCCl
Product: Cn1cc(CC(N)=O)c2ccc(-n3ccnc3)cc21
Reaction time: 24 h
Yield: 67 %

Procedure:
(6-Imidazol-1-yl-1-methyl-1H-indol-3-yl)acetic acid methyl ester (230 mg, 0.85 mmol) was suspended in concentrated NH4OH (5 mL) in a 100 mL flask and stirred in a sealed flask for 24 h. Lyophilization of the mixture gave a crude product, which was chliomatographed on silica gel using 2-8% MeOH in CH2Cl2 to give (6-imidazol-1-yl-1-methyl-1H-indol-3-yl)acetamide (145 mg, 67%).
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: NN
Reactant: O=C1NC(=O)c2c(CCCCCCCCN3CCCCC3)cccc21
Solvent: CO
Product: NCCCCCCCCN1CCCCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 8-piperidinyloctylphthalimide (274 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH3:22])=[CH:14][CH:15]=1)#[N:2]
Reactant: COC(=NC#N)c1ccccn1
Reactant: Cc1ccc(CCN)cc1
Solvent: CO
Product: Cc1ccc(CCN=C(NC#N)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 ml), 2-(p-tolyl)ethylamine (0.47 g, 3.5 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from methanol-diethyl ether to give the title compound (0.76 g, 2.9 mmol, yield: 93%) as colorless crystals.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[C:22]([C:24](O)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1>C(Cl)Cl>[ClH:4].[N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[C:22]([C:24]([Cl:7])=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cc(-c2ccncc2)nc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2ccncc2)nc2ccccc12
Temperature: -10 °C
Reaction time: 72 h
Yield: 126 %

Procedure:
1.3 ml (10.4 mmol) of oxalyl chloride were dissolved in 60 ml of CH2Cl2. The solution was cooled at −10° C. and 3.0 g (14.4 mmol) of 2-(4-pyridyl)quinoline-4-carboxylic acid hydrochloride were added portionwise. The reaction mixture was left 72 hours at room temperature and then evaporated to dryness to yield 4.0 g of the title compound, used without further purification.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH:48]([NH:51][CH3:52])([CH3:50])[CH3:49]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([N:51]([CH:48]([CH3:50])[CH3:49])[CH3:52])=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: CNC(C)C
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C(C)C)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with isopropyl-methyl-amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H51Cl2N6O3 [(M+H)+] 721.3394, observed 721.3399.
Reaction SMILES: C(N1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=O.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C.C(OCC)C>[CH2:13]([O:20][C:13]([CH:14]1[CH2:19][C:11](=[CH2:12])[CH2:15]1)=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=C1CC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.2 %

Procedure:
A suspension of 1,1′-carbonyldiimidazole (1.59 g, 9.81 mmol) in ethyl acetate (5 ml) was added in portions to a solution of the product of Preparation 12 (1 g, 8.9 mmol) in ethyl acetate (5 ml). Gentle effervescence was observed. The mixture was stirred at room temperature for about 1.5 hours, benzyl alcohol (1.11 ml, 10.7 mmol) added and stirring continued overnight. The solution was diluted with diethyl ether (20 ml), washed with water (2×10 ml), dried over magnesium sulphate and evaporated in vacuo to a colourless liquid which was purified by filtering through 10 g SiO2, eluting with dichloromethane, to give the title compound as a colourless oil (1.246 g, 69%).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:33]=[CH:32][C:12]([CH2:13][NH:14][CH2:15][CH2:16][C:17]4[CH:31]=[CH:30][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=4)=[CH:11][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.Cl[C:35]1[O:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1>>[O:36]1[C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=[C:35]1[N:14]([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[N:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[O:8][N:7]=2)=[CH:33][CH:32]=1)[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([OH:25])=[O:24])=[CH:30][CH:31]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(-c3noc(C4CC4)n3)cc2)cc1
Reactant: Clc1nc2ccccc2o1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(-c3noc(C4CC4)n3)cc2)c2nc3ccccc3o2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 2-chlorobenzoxazole.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:27])[C:9]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:26])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:24](=[O:26])[CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:27])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC1(C)c2cc(OCC(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetic acid (Compound A8-7, 30 mg, 0.083 mmol), piperazine-1-carboxylic acid tert-butyl ester (31 mg, 2 eq.), and HOBt (30 mg, 3 eq.) were dissolved in 0.5 ml DMF, added with EDC (48 mg, 3 eq.), and stirred at room temperature overnight. Thereafter, the solvent was removed under reduced pressure and the resulting residues were purified by preparative TLC to obtain the title compound (20 mg).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]1[CH:15]=[C:16]([O:21][CH3:22])[C:17]([NH2:20])=[N:18][CH:19]=1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[S:6][C:2]([C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)=[C:3]([C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([NH2:20])=[N:18][CH:19]=3)[N:4]=2)=[CH:8][CH:9]=1
Reactant: COc1cc(-c2nc(-c3ccc(F)cc3)sc2Br)cnc1N
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2nc(-c3ccc(F)cc3)sc2-c2ccncc2)cnc1N
Yield: 55.3 %

Procedure:
A mixture of 5-(5-bromo-2-(4-fluorophenyl)thiazol-4-yl)-3-methoxypyridin-2-amine (40 mg, 0.11 mmol), 4-pyridineboronic acid (39 mg, 0.32 mmol), and, and aqueous 2.0 M Na2CO3 solution (0.6 mL) in DME (1.8 mL) was sparged with Ar for 3 min. Tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) was added and the reaction mixture was sparged with Ar for 1 min. The reaction was sealed and irradiated at 115° C. for 15 min in a microwave reactor. The reaction mixture was partitioned with EtOAc (25 mL) and saturated aqueous NaHCO3 solution (25 mL). The separated organic layer was washed with saturated aqueous NaHCO3 solution (25 mL), brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC, which after lypholization, provided 23 mg of the titled compound as the TFA salt: LCMS (m/z): 378.9 (MH+), tR=0.57 min.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([NH2:14])[N:3]=1.[C:15](#[N:17])C>>[NH2:14][C:4]1[N:3]=[C:2]([C:15]#[N:17])[C:7]([CH3:8])=[C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:5]=1
Reactant: Cc1c(Cl)nc(N)nc1-c1ccco1
Reactant: CC#N
Product: Cc1c(C#N)nc(N)nc1-c1ccco1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of 4-chloro-6-(2-furyl)-5-methylpyrimidine-2-amine (80 mg, 0.38 mmol) in acetonitrile (4 mL) was treated with polymer supported cyamide (0.636 mg, 1.91 mmol), stirred at 140° C. in the microwave for 30 min, filtered to remove the resin and the filter cake washed with acetonitrile. The filtrate was concentrated in vacuo to give the title compound (50 mg, 65%) as off-white solid; NMR δH (400 MHz, DMSO) 2.48 (3H, s), 6.75 (1H, dd, J 1.7, 3.5 Hz), 7.04 (2H br s), 7.28 (1H, dd, J 0.7, 3.5 Hz) and 8.00 (1H, dd, J 0.7, 1.7 Hz); M/Z 201 (M=H)+; HPLC 1.1 min. (50/80).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([CH:11]=O)=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=2)[CH2:3][CH2:2]1.[F:15][C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[C:18]([F:26])[C:17]=1[NH2:27].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH:1]1([NH:4][C:5]2[C:10]([CH:11]=[N:27][C:17]3[C:18]([F:26])=[C:19]([O:24][CH3:25])[CH:20]=[C:21]([O:22][CH3:23])[C:16]=3[F:15])=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CSc1ncc(C=O)c(NC2CC2)n1
Reactant: COc1cc(OC)c(F)c(N)c1F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(F)c(N=Cc2cnc(SC)nc2NC2CC2)c1F
Reaction time: 48 h
Yield: 70 %

Procedure:
To a solution of the 7.00 g (33.4 mmol) of 4-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 500 mL of toluene was added 6.33 g 33.4 mmol, 1 equivalent) of 2,6-difluoro-3,5-dimethoxy-phenylamine and 1.94 g (8.36 mmol, 0.25 equivalents) of camphorsulfonic acid. The reaction was warmed to reflux and the formed water was removed with the aid of a Dean-Stark trap. After reacting for 48 hours, the reaction was concentrated in vacuo. The residue was stirred with ether and filtered. The filter pad was dissolved in dichloromethane, stirred with silica gel, and concentrated in vacuo. The residue was placed in the sample injection module of a Biotage FLASH 75 chromatographic apparatus. Chromatography of the crude material down a Biotage 500 g silica gel column with 2:1 hexane/ethyl acetate, then 1:1 hexane/ethyl acetate and finally 9:1 ethyl acetate/ethanol gave 8.92 g (70%) of title compound as a solid: mp 172° C.–174° C. MS (APCI) (m+1)/z 381.0 Analysis calculated for C17H18aF2N4SO2: C, 53.67; H, 4.77; N, 14.73. Found: C, 53.54; H, 4.58; N, 14.61.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]3[CH2:17][CH2:16][CH2:15][CH:12]32)=[CH:7][CH:6]=1)([O-])=O.Cl.[H][H]>CO.[Pd]>[NH2:2][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]3[CH2:17][CH2:16][CH2:15][CH:12]32)=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CCCN1CC2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)C1CCCN1CC2
Yield: 104.9 %

Procedure:
To 9-nitro-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline hydrochloride (Example 31(b), 2.0 g) in methanol (100 ml) was added concentrated hydrochloric acid (0.67 ml) and 5% palladium on carbon (200 mg). The mixture was hydrogenated at 50 psi on a Parr Hydrogenator. Hydrogen uptake was complete in 1.0 h. The catalyst was filtered off and the solvent removed under reduced pressure. The residue was dissolved in water, the solution basified with 2.5M sodium hydroxide and the product extracted into dichloromethane. The extracts were dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure to yield the title compound as a thick oil (1.55 g).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[O:15])[O:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[CH2:8]([C:9]1[CH:10]=[C:11]([CH:14]=[O:15])[O:12][CH:13]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc(C#Cc2ccccc2)co1
Agent: [Pd]
Solvent: CO
Product: O=Cc1cc(CCc2ccccc2)co1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.5 %

Procedure:
To a solution of 4-phenylethynyl-furan-2-carbaldehyde (1.54 g, 7.84 mmol) in MeOH was added palladium on carbon (Pd/C) (154 mg, 10% Pd by weight). A vacuum was applied to the reaction mixture and back filled with H2 4 times. The reaction was then allowed to stir at rt for 14 h under an atmosphere of H2 before being filtered through a plug of Celite® with EtOAc. The reaction was then concentrated in vacuo to give 4-phenethyl-furan-2-carbaldehyde as a colorless oil (1.53 g, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 9.59 (d, J=0.6 Hz, 1 H) 7.40 (d, J=0.8 Hz, 1 H) 7.28-7.34 (m, 2 H) 7.20-7.26 (m, 1 H) 7.14-7.20 (m, 2 H) 7.05 (d, J=0.6 Hz, 1 H) 2.87-2.94 (m, 2 H) 2.78-2.85 (m, 2 H).
Reaction SMILES: [NH2:1][NH2:2].[C:3]([O:7][C:8]([NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[C:19]([CH:24]=[C:25]([Cl:27])[N:26]=2)[C:20](OC)=[O:21])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)(C)C>[Cl:27][C:25]1[N:26]=[C:17]([N:14]2[CH2:13][CH2:12][CH:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:4])([CH3:5])[CH3:6])[CH2:16][CH2:15]2)[CH:18]=[C:19]([C:20]([NH:1][NH2:2])=[O:21])[CH:24]=1
Reactant: COC(=O)c1cc(Cl)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1
Reactant: NN
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C(=O)NN)cc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Hydrazine (0.55 ml 17.0 mmol) was added to a solution of methyl 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6-chloroisonicotinate (Intermediate 23, 0.15 g, 0.40 mmol) in isopropanol (3 ml). The mixture was stirred at room temperature overnight then the isopropanol was removed in vacuo to give the title product (130 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1
Reaction time: 5 h
Yield: 87.5 %

Procedure:
4-Bromobenzoic acid (9.98 kg, 48 mol) was suspended in 40 kg of methanol. Sulfuric acid (2 kg, 20 mol) was added and the mixture was heated under reflux for approximately 5 hours. The mixture was cooled over 10 hours to -10° C. and allowed to stand for 5 hours giving a crystalline product. The product was isolated by filtration and the filter cake was washed with methanol (2×3 L). Drying gave methyl 4-bromobenzoate (9.97 kg, 42 mol), m.p. 78°-78.7° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][O:1][N:33]3[C:34](=[O:43])[C:35]4=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]4[C:37]3=[O:38])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1ccc2ncccc2c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1ccc2ncccc2c1
Reaction time: 8 h
Yield: 78.6 %

Procedure:
6-(hydroxymethyl)quinoline (520 mg, 3.27 mmol), triphenyl phosphine (900 mg, 3.44 mmol, 1.05 equiv) and N-hydroxyphthalimide (560 mg, 3.43 mmol, 1.05 equiv) were dissolved in 25 mL of dry THF. Diethylazodicarboxylate (574 μL, 3.63 mmol, 1.11 equiv) was then added dropwise and the reaction was stirred overnight. The reaction mixture filtered to give a white solid. The filtrate was concentrated and a second crop of material was obtained by triturating with Et2O. This was combined with the original solid and recrystallization from EtOH gave the desired product (782 mg) as a fluffy white solid. MS(CI) m/e 305 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](B(O)O)=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)[CH:3]=2)=[CH:21][N:20]=1
Reactant: Cc1cccc(-c2cc(Cl)c3cccnc3n2)n1
Reactant: OB(O)c1cncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-c2cc(-c3cncc4ccccc34)c3cccnc3n2)n1
Yield: 68 %

Procedure:
190 mg 4-chloro naphthyridine from example 3, 341 mg 4-isoquinoline boronic acid pinacole ester, 473 mg sodium carbonate were dissolved with 20 ml dioxan and 5 ml water, flushed with nitrogen, and 86 mg tetrakistriphenylphosphine palladium(0) were added. After 90 min reflux, workup as in example 20 yielded a grey-brownish oil, which was crystallized with ether to give 176 mg correct product as a brownish powder with correct LC_MS: M+H+ 349 and Rf˜1.76 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Cl:18][CH:19]([Cl:22])[CH2:20]O>>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:20][CH:19]([Cl:22])[Cl:18])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Reactant: OCC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)OCC(Cl)Cl)C1(C)C

Procedure:
Using the procedure of Step F of Example 9, 4.8 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[(Z)3-hydroxy-3-oxo-1-propenyl]-cyclopropane-carboxylate and 2 ml of 2,2-dichloroethanol were reacted to obtain after elution with a 9-1 mixture of cyclohexane-ethyl acetate 5.6 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[(Z)3-oxo-3-(2,2-dichloroethoxy)-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[N:12]=[C:11](Cl)[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:22][CH2:23][O-:24].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[N:12]=[C:11]([O:24][CH2:23][CH3:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CC[O-]
Reactant: Clc1nc(C2CCNCC2)nc2c1[nH]c1cc(Br)ccc12
Agent: [Na+]
Solvent: O
Product: CCOc1nc(C2CCNCC2)nc2c1[nH]c1cc(Br)ccc12

Procedure:
300 mg (0.82 mmol) 7-bromo-4-chloro-2-(4-piperidyl)-5H-pyrimido[5,4-b]indole was mixed with an excess of 2 M NaOEt and kept at reflux for 2 h. Then, water was added and the solvent was removed in vacuo. Following LC (CH2Cl2/MeOH, 0-50%), 160 mg (52%) of the title substance was obtained ESI-MS [m/z]: 375, 377 [M+H]+