Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[CH2:30]O.[NH2:33][C@@H:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[CH2:30][NH:33][C@@H:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1
Reactant: OCc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 52 %

Procedure:
The desired compound was prepared according to the procedure of Example B191 step A, using [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methanol trifluoroacetate and tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate as the starting materials in 52% yield. LCMS for C28H34ClN6O2(M+H)+: m/z=521.3.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=4)[N:19]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:18]=3)[C:14]([C:40]#[N:41])=[CH:13][N:12]=2)[CH3:9])[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl>[NH2:46][CH:2]1[CH2:7][CH2:6][CH:5]([C@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=4)[N:19]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:18]=3)[C:14]([C:40]#[N:41])=[CH:13][N:12]=2)[CH3:9])[CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(=O)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reactant: [NH4+]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(N)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
2-((R)-1-(4-oxocyclohexyl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (105 mg, 0.1802 mmol) was disolved in methanol (5 mL) and dichloromethane (5 mL). Ammonium acetate (138.9 mg, 118.7 μL, 1.802 mmol), followed by sodium triacetoxyborohydride (38.19 mg, 0.1802 mmol) were added and the reaction mixture was stirred for 4 hours at room temperature. The mixture was partitioned between dichloromethane and a saturated solution of sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness to afford the desired product as a yellow solid (95 mg, 90% yield).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].N[CH2:20][CH2:21][S:22][CH2:23][N:24]1N=CC=N1>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:23]1[S:22][CH:21]=[CH:20][N:24]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reactant: NCCSCn1nccn1
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene with an excess of 2-[(2-aminoethyl)thiomethyl]triazole according to the procedure of Example 3, results in the production of 1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene, m.p. 110°-120° (from acetonitrile).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1C[CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1>N1C=CC=CC=1>[C:5]([O:4][CH:1]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:2]1)(=[O:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 62 %

Procedure:
4.75 g of di-tert-butyl dicarbonate are added to a mixture of 2 g of 4-hydroxypiperidine in 4 ml of water and 13.8 ml of a 2N aqueous sodium hydroxide solution. The reaction medium is stirred at ambient temperature for 2 hours and then 50 ml of chloroform are added. The two phases are separated and the organic phase is washed with an aqueous 25% NH4OH solution and then with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and evaporated, so as to give 4 g of 2-methylpropan-2-yl 4-hydroxypiperidine-1-carboxylate in the form of a colourless oil. 2.84 g of acetic anhydride are added to a solution of 4.0 g of 2-methylpropan-2-yl 4-hydroxypiperidine-1-carboxylate in 6 ml of pyridine. The reaction medium is stirred for hours at ambient temperature and then concentrated to dryness. The residue is taken up in dichloromethane and an aqueous 25% NH4OH solution. The two phases are separated and the organic phase is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and MeOH (95/5), so as to obtain 3 g of 2-methylpropan-2-yl 4-(acetyloxy)piperidine-1-carboxylate in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:15])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:16][O:17]C(Cl)Cl.Cl>ClCCl.C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:15])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:7][C:8]=1[CH:16]=[O:17]
Reactant: COc1ccc(C2(C)CCOCC2)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C2(C)CCOCC2)cc1C=O
Reaction time: 0.33 h
Yield: 122.3 %

Procedure:
A solution of 4-(4-methoxyphenyl)-4-methyltetrahydro-2H-pyran (0.518 g, 2.51 mmol) in dichloromethane (12.0 mL) was cooled to −15° C., and titanium tetrachloride (1.22 mL, 11.0 mmol) was added dropwise thereto. After stirring the mixture for 20 minutes, dichloromethyl methyl ether (0.336 mL, 3.77 mmol) was added dropwise thereto. After stirring the mixture for 1 hour, 1 mol/L hydrochloric acid was added to stop the reaction. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and then with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure to obtain 0.719 g of the crude product containing the captioned compound.
Reaction SMILES: Br[CH:2]([CH3:9])[CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.Cl[C:11]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1>O1CCCC1.[Zn]>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH:2]([C:11]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1)[CH3:9]
Reactant: Fc1cnc(Cl)nc1
Reactant: CC(Br)CC1OCCO1
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(CC1OCCO1)c1ncc(F)cn1
Temperature: 40 °C
Reaction time: 4 h
Yield: 22.9 %

Procedure:
To a stirring suspension of activated “Rieke” zinc in tetrahydrofuran (21 ml, 1.53M) was added 2-(2-bromopropyl)-1,3-dioxolane (6.6 g) in tetrahydrofuran (50 ml), a rise in temperature from 21° C. to 40° C. was observed, heated at 40° C. for 1 hour then allowed to cool to ambient temperature before adding 2-chloro-5-fluoropyrimidine (3 g) and [1,2-Bis(diphenylphosphino)-propane]dichloronickel(II)chloride (368 mg). The mixture was stirred at ambient temperature for 4 hours then filtered through a pad of celite and the filtrate evaporated under reduced pressure. Flash chromatography (silica gel, haxane-25% ethyl acetate in hexanes) then gave the product as a pale yellow oil (1.1 g); 1H NMR (d6-DMSO): 8.81 (s, 2H), 4.73 (dd, 1H), 3.66–3.87 (m, 4H), 3.21–3.30 (m, 1H), 2.19 (ddd, 1H), 1.83 (ddd, 1H), 1.27(d, 3H); m/z 213 (M+1).
Reaction SMILES: [C:1]1([C:7]([O:9][C@@H:10]2[CH2:20][O:19][C@@H:12]3[C@@H:13]([OH:18])[C@@H:14]([O:17][C@H:11]23)[O:15][CH3:16])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21]I>CN(C=O)C.C(OCC)(=O)C.[Ag-]=O>[CH3:21][O:18][C@@H:13]1[C@H:12]2[O:19][CH2:20][C@@H:10]([O:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[C@H:11]2[O:17][C@H:14]1[O:15][CH3:16]
Reactant: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OC(=O)c2ccccc2)[C@H]1O
Reactant: CI
Agent: O=[Ag-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OC(=O)c2ccccc2)[C@H]1OC
Temperature: 60 °C
Yield: 76 %

Procedure:
A mixture of methyl 3,6-anhydro-5-O-(phenylcarbonyl)-β-D-glucofuranoside (1.03 g, 3.7 mmol), silver (I) oxide (0.85 g, 3.7 mmol) and methyl iodide (0.34 mL, 5.5 mmol) in DMF (2 mL) was heated at 60° C. for 1 hour. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (50 mL), filtered over celite, adsorbed on silica gel (10 g) and purified by flash chromatography (silica gel, 5-30% ethyl acetate-hexane) to give methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-D-glucofuranoside as a colorless oil, 0.82 g, 76% yield. 1H NMR (400 MHz; CDCl3): 8.11-8.09 (d, 2H), 7.60-7.56 (m, 1H), 7.46-7.44 (m, 2H), 5.24-5.20 (m, 1H), 5.18-5.09 (tr, 1H), 4.99 (s, 1H), 4.61-4.60 (d, 1H), 4.21-4.17 (tr, 1H), 4.08-4.03 (tr, 1H), 3.81 (s, 1H), 3.40 (s, 3H), 3.57 (s, 3H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)C>CS(C)=O>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[CH:25]1[CH2:30][CH2:29][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:27][CH2:26]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1cccc2c(C3CCNCC3)c[nH]c12
Solvent: CCO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3c(Cl)cccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.406 g, 2.13 mmol) and 7-chloro-3-(piperidin-4-yl)-1H-indole (0.500 g, 2.13 mmol) using ethanol as reaction solvent. Yield 0.325 g (35%) as a colorless powder. mp 186°-189° C. FDMS m/e=423 (M+ of free base). α[D]589 =+8.44 (c=1.09, dimethylsulfoxide).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])O1.C([O-])([O-])=O.[K+].[K+].CC#N>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.O>[OH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: CC(C)COC(=O)N1CCN(c2cc(Cl)ncn2)CC1
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: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)COC(=O)N1CCN(c2cc(-c3ccccc3O)ncn2)CC1
Temperature: 130 °C

Procedure:
A mixture of isobutyl 4-(6-chloropyrimidin-4-yl)piperazine-1-carboxylate (0.10 g, 0.33 mmol), 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (87 mg, 0.11 mmol), Pd(PPh3)4 (3.8 mg, 3.3 μmol), K2CO3 (91 mg, 0.66 mmol), CH3CN (1 mL), and H2O (0.1 mL) was sealed in a microwave reactor vial. The reaction mixture was heated by microwave irradiation at 130° C. for two minutes. The reaction was filtered and purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give isobutyl 4-(6-(2-hydroxyphenyl)pyrimidin-4-yl)piperazine-1-carboxylate. LC/MS: m/z 357.3 (M+H)+ at 2.72 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)C.Cl.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1>C(O)CCC.C(OC)(C)(C)C>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:31]=[CH:32][C:33]([N:36]2[C:4](=[O:3])[C:6]3=[C:7]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=4)[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]3=[N:37]2)=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(NN)cc1
Reactant: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nc2ccccc2c1Cl
Agent: Cl
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: COC(=O)c1ccc(-n2nc3c4ccccc4[nH]c(-c4ccc([N+](=O)[O-])cc4)c-3c2=O)cc1
Yield: 76.6 %

Procedure:
4-Chloro-2-(4-nitrophenyl)-quinoline-3-carboxylic acid ethyl ester (2.86 g, 0.008 mol) and 4-hydrazino-benzoic acid methyl ester hydrochloride (1.7 g, 0.008 mol) were stirred in n-butanol (70 mL) at 120° C. for 24 h. The bright orange suspension was diluted with tert-butylmethyl ether, filtered, washed with cold heptane and left to dry under suction to yield 4-[4-(4-nitrophenyl)-3-oxo-3,5-dihydropyrazolo[4,3-c]quinolin-2-yl]-benzoic acid methyl ester (2.7 g, 76%) as an orange solid, LCMS m/z 441.35 [M+H]+ @ RT 1.66 min: 84% purity.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]([C:11](SC)=[CH:12][N+:13]([O-:15])=[O:14])[CH2:8][CH2:9][CH3:10])[CH2:2]1.[CH2:18]([NH2:20])[CH3:19]>>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]([C:11]([NH:20][CH2:18][CH3:19])=[CH:12][N+:13]([O-:15])=[O:14])[CH2:8][CH2:9][CH3:10])[CH2:2]1
Reactant: CCCN(CC1CCOC1)C(=C[N+](=O)[O-])SC
Reactant: CCN
Product: CCCN(CC1CCOC1)C(=C[N+](=O)[O-])NCC
Temperature: 25 °C

Procedure:
A mixture comprising 0.25 g of 1-[N-{(tetrahydro-3-furanyl)methyl}-N-propylamino]-1-methylthio-2-nitroethylene and 1 ml of 70% aqueous ethylamine solution was stirred for an hour at room temperature. After concentration of the mixture under a reduced pressure, the reaction fluid was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=7/1) to obtain 0.25 g of 1-[N-{(tetrahydro-3-furanyl)methyl}-N-propylamino]-1-ethylamino-2-nitroethylene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[N:23][CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:31]CN(CC)CC.C=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:25]5[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]5)=[N:23][CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCN(CC)CC
Reactant: COc1ccc(-c2nn3c(-c4cnc(N5CCNCC5)nc4)cnc3s2)cc1OC
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-c2nn3c(-c4cnc(N5CCN(C)CC5)nc4)cnc3s2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.1 %

Procedure:
To a mixture of 2-(3,4-Dimethoxy-phenyl)-5-(2-piperazin-1-yl-pyrimidin-5-yl)-imidazo[2,1-b][1,3,4]thiadiazole (52 mg, 0.113 mmol, 1 eq), Et3N (0.032 mL, 0.226 mmol, 2 eq), formaldehyde (0.102 mL, 1.36 mmol, 12 eq) and acetic acid (0.02 mL, 0.136 mmol, 1.2 eq) in MeOH (2 mL) was added Sodium cyanoborohydride (0.1 g, 1.58 mmol, 14 eq). The reaction mixture was stirred at rt for 2 h. Solvents were evaporated to dryness and the residue was dissolved in sat NaHCO3/EtOAc. Layers were separated and the aqueous layer was extracted once with EtOAc. The combined organic layers were dried, filtered and evaporated. The residue was purified by HPLC to give the desired product (6 mg, 12%). HPLC-MS: (5-40% B in 8 min, 0.8 mL/min, 50° C.): tR=4.64 min, [M+H]+ m/z 438.2; 1H NMR (300 MHz, DMSO) δ 8.98 (s, 2H), 7.70 (s, 1H), 7.56 (dd, J=8.4, 2.0 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.80 (m, 4H), 2.38 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8](O)=[O:9])[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[N:4]1)[CH3:2].[CH3:35][CH2:36][N:37]=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.Cl.C(N)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:36]([NH:37][C:8]([C:6]1[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1)=[O:9])[CH3:35]
Reactant: CCn1cc(C(=O)O)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reactant: CCN=C=NCCCN(C)C
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCNC(=O)c1cn(CC)nc1NS(=O)(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 16 h

Procedure:
To a solution of the title compound of Example 3 (0.15 g, 0.31 mmol), EDCl (0.12 g, 0.62 mmol), 1-hydroxybenzotriazole (0.42 g, 0.31 mmol) and TEA (0.2 g, 1.5 mmol) in DCM, is added ethylamine hydrochloride (0.5 g, 0.62 mmol) at RT. The reaction mixture is stirred for 16 h. The reaction mixture is diluted with ethyl acetate, washed with 1N hydrochloric acid, water and brine. The organic filtrate is concentrated, the crude is chromatographed using 25% ethyl acetate in hexanes to provide 1-ethyl-3-{4-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzenesulfonylamino}-1H-pyrazole-4-carboxylic acid ethyl amide as a crystalline solid: MS [m/z] 508.1 [M-1]−.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: NC(=O)c1ccccc1N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccccc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (6.91 g) and 2-aminobenzamide (11.8 g), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide was isolated as a white solid (6.2 g, 70% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.67 (d, J=4.03 Hz, 1 H), 7.17 (td, J=7.59, 1.10 Hz, 1 H), 7.47 (d, J=8.05 Hz, 2 H), 7.57 (td, J=7.87, 1.46 Hz, 1 H), 7.75 (d, J=4.03 Hz, 1 H), 7.78 (s, 1 H), 7.83 (dd, J=8.05, 1.46 Hz, 1 H), 7.98 (dt, J=8.69, 1.97 Hz, 2 H), 8.30 (s, 1 H), 8.44 (dd, J=8.33, 1.01 Hz, 1 H), 12.32 (s, 1 H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=[O:33])[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[NH2:34][C@H:35]([CH2:40]O)[C:36]([CH3:39])([CH3:38])[CH3:37].C(O)(=O)C>ClCCl>[CH3:37][C:36]([C@@H:35]1[N:34]2[C:3](=[O:4])[C:5]3[N:6]([CH:7]=[C:8]([C:20]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[O:30])[C:9](=[O:19])[C:10]=3[O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:31][C@H:32]2[O:33][CH2:40]1)([CH3:39])[CH3:38]
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: CC(C)(C)[C@H](N)CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N21
Yield: 85.5 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (41 mg, 0.09 mmol) and freebased L-tert-leucinol (59 mg, 0.50 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (3S,11aR)-3-(1,1-dimethylethyl)-N-[(4-fluorophenyl)methyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (40 mg, 85%). This material was hydrogenated in a second step as described in example Z-2 to give (3S,11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (32 mg, 97%) as a tinted white solid. 1H NMR (CDCl3) δ 11.15 (br, 1H), 10.32 (s, 1H), 8.38 (s, 1H), 7.29 (m, 2H), 6.98 (m, 2H), 5.43 (m, 1H), 4.58 (m, 2H), 4.36 (m, 2H), 4.21 (m, 1H), 3.99 (m, 1H), 3.79 (m, 1H), 1.02 (s, 9H); ES+ MS: 430 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=4[CH:17]=[C:16]([C:26]4[O:30][CH:29]=[N:28][C:27]=4[C:31]([OH:33])=O)[CH2:15][N:14]3[C:34]=2[CH:35]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:36]1([C:12]2[C:11]3[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:35][C:34]=3[N:14]3[CH2:15][C:16]([C:26]4[O:30][CH:29]=[N:28][C:27]=4[C:31]([N:64]4[CH2:69][CH2:68][O:67][CH2:66][CH2:65]4)=[O:33])=[CH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=4[C:13]=23)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: C1COCCN1
Reactant: COc1ccc2c(c1)C=C(c1ocnc1C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(c1ocnc1C(=O)N1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Yield: 109 %

Procedure:
5-(10-(tert-Butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1,3-oxazole-4-carboxylic acid (185 mg, 0.334 mmol) was dissolved in DMF (3.2 ml), and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium tetrafluoroborate (193 mg, 0.600 mmol) was added. The reaction was stirred capped at room temperature for 25 minutes and DMAP (163 mg, 1.334 mmol) was dissolved in the reaction then morpholine (0.058 ml, 0.667 mmol) was added. The reaction was capped and stirred at room temperature overnight. The reaction was poured into 30 ml of water and extracted with dichloromethane. The organic layer was washed sequentially with 0.1M aqueous citric acid, 0.1M aqueous NaH2PO4, then dried over anhydrous sodium sulfate. The sample was filtered, volatiles removed and the sample dried in vacuuo to obtain 227 mg of an amorphous orange solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.16-1.50 (m, 7H) 1.53-1.61 (m, 6H) 1.62 (s, 10H) 1.76 (d, J=10.38 Hz, 2H) 1.83-2.15 (m, 5H) 3.40-3.84 (m, 7H) 3.83-3.95 (m, 5H) 4.40 (d, J=11.60 Hz, 1H) 5.64 (d, J=12.21 Hz, 1H) 6.97 (d, J=2.75 Hz, 1H) 7.05 (dd, J=8.39, 2.59 Hz, 1H) 7.50 (d, J=8.55 Hz, 1H) 7.53 (s, 1H) 7.65 (d, J=8.24 Hz, 1H) 7.77-7.86 (m, 2H) 7.97-8.04 (m, 1H) 8.10 (s, 1H). LC-MS retention time 2.64 min m/z 624 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 2 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.