Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1CCCC1=O.[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12](I)=[CH:11][N:10]=1.[NH4+]>[C-]#N.[Zn+2].[C-]#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.C(OCC)(=O)C>[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([C:1]#[N:2])=[CH:11][N:10]=1
Reactant: Nc1cc(Cl)c(I)cn1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: N#Cc1cnc(N)cc1Cl
Temperature: 132.5 °C
Reaction time: 5 h

Procedure:
1-Methyl-2-pyrrolidone (20 ml), zinc cyanide (0.49 g, 4.17 mmol) and tetrakis(triphenylphosphine)palladium (1.3 g, 1.12 mmol) were added to 2-amino-4-chloro-5-iodopyridine (1.93 g, 7.58 mmol) synthesized in Production example 215-2; and the reaction mixture was stirred at 130-135° C. for 5 hours. Approximately 0.28% of aqueous ammonium (100 ml) and ethyl acetate was added to the reaction mixture; and the organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure and the residue was filtrated by silica gel column chromatography (Fuji Silysia NH, ethyl acetate). After concentration under reduced pressure, a solvent mixture (ether:hexane=1:1) was added to the residue, and stirred; and the solid was filtered off to yield the title compound as crystals (680 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[CH:6]=[C:5]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:4]=1.S([CH2:38][N+:39]#[C-:40])(C1C=CC(C)=CC=1)(=O)=O.COCCOC>O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([NH:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH:6]=[C:7]([C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]3[O:13][CH:40]=[N:39][CH:38]=3)[CH:10]=2)[N:8]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(CCNc2cc(-c3cccc(C=O)c3)nc(OC)n2)cc1
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CCNc2cc(-c3cccc(-c4cnco4)c3)nc(OC)n2)cc1
Temperature: 85 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
In a tube is combined 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde (200 mg, 0.55 mmol), tosylmethylisocyanide (119 mg, 0.61 mmol), Ambersep 900 OH resin (1 g), ethylene glycol dimethyl ether (3.5 mL) and water (3.5 mL). The tube is sealed and the mixture is heated to 85° C. and stirred for 18 hours. The mixture is allowed to cool to ambient temperature and filtered to remove the resin, and washed the resin with 10 mL methanol. The combined filtrate and washings are concentrated by rotary evaporator and the residue is subjected to flash column chromatography on silica gel eluting with 10 to 40% EtOAc in heptane gradient, to afford [2-methoxy-6-(3-oxazol-5-yl-phenyl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [65 mg, 29.4%, Example 11(b)]. LCMS: RT=2.59 minutes MS: 403 (M+H). IC50=2.6 nM
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.[N+:20]([C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26])([O-:22])=[O:21].C(N(CC)CC)C.CCCCCC>C(Cl)Cl>[N+:20]([C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1)=[O:26])([O-:22])=[O:21]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A portion (200 mg) of the compound obtained in Example 81 was suspended in methylene chloride (10 ml) and to the suspension were added 2-nitrobenzoyl chloride (0.18 ml) and triethylamine (0.11 ml) under cooling with ice. The mixture was stirred for 30 minutes at room temperature. n-Hexane was added to the reaction mixture, and the crystals were collected by filtration and washed with water and n-hexane successively to yield 260 mg (81%) of the titled compound as brown crystals.
Reaction SMILES: CCC(O)CCCCCCC.CCCC(O)CCCCCC.[CH3:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CCC(=O)CCCCCCC.CCCC(=O)CCCCCC>>[CH3:23][CH:24]([OH:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCC(C)=O
Agent: CCCCCCC(=O)CCC
Agent: CCCCCCC(O)CCC
Agent: CCCCCCCC(=O)CC
Product: CCCCCCCCC(C)O

Procedure:
3-decanol and 4-decanol (1.10 mmol); 2-decanone (1.73 mmol); 3-decanone and 4-decanone (1.41 mmol).
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:16]3[S:21][C:20]([CH2:22][N:23]4[CH2:28][C@H:27]([CH3:29])[NH:26][C@H:25]([CH3:30])[CH2:24]4)=[CH:19][C:17]=3[N:18]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:46](Cl)(=[O:48])[CH3:47]>ClCCl>[C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[C:16]3[S:21][C:20]([CH2:22][N:23]4[CH2:24][C@H:25]([CH3:30])[N:26]([C:46](=[O:48])[CH3:47])[C@H:27]([CH3:29])[CH2:28]4)=[CH:19][C:17]=3[N:18]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(Cc2cc3nc(-c4cccc(O[Si](C)(C)C(C)(C)C)c4)nc(N4CCOCC4)c3s2)C[C@H](C)N1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1[C@H](C)CN(Cc2cc3nc(-c4cccc(O[Si](C)(C)C(C)(C)C)c4)nc(N4CCOCC4)c3s2)C[C@@H]1C
Reaction time: 8 h

Procedure:
To a solution of 2-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-6-((3R,5S)-3,5-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (80 mg, 0.14 mmol) in dichloromethane (5 mL) was added triethylamine (40 μL, 2.0 equivalents) followed by acetyl chloride (15 μL, 1.5 eq.). After stirring overnight, the reaction mixture was diluted with dichloromethane, washed with aqueous sodium carbonate solution, dried (MgSO4) and the solvent removed in vacuo to yield 1-((2R,6S)-4-{2-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl}-2,6-dimethyl-piperazin-1-yl)-ethanone (80 mg) as a white solid. Removal of the tert-butyldimethylsilyl protecting group was performed as described above to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=O)=[CH:15][CH:14]=1>C(O)(=O)C>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[C:19]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=3)=[N:1][C:2]3[C:9](=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=3)[N:10]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3ccc(C#N)cc3nc2-c2ccc(OC)cc2)cc1
Reaction time: 3 h
Yield: 72.6 %

Procedure:
A solution of 3,4-diaminobenzonitrile (50 mg, 0.30 mmol, 1.00 equiv, 80%) and 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (89 mg, 0.33 mmol, 1.00 equiv) in acetic acid (5 mL) was stirred for 30 min at 30° C. in an oil bath, then at 130° C. for 3 h. The reaction was quenched with 10 mL of water. The solids were collected by filtration and dried in an oven under reduced pressure, yielding 80 mg (72%) of 2,3-bis(4-methoxyphenyl)quinoxaline-6-carbonitrile as a yellow solid.
Reaction SMILES: [CH:1](=[C:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[C:12]([Cl:25])[CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].O>CO.CN(C)C=O.[Pd]>[CH2:1]([CH:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[C:12]([Cl:25])[CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=c1[nH]c2c3cc(Cl)ccc3c(=Cc3ccccc3)c2n2ccnc12
Agent: [Pd]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1ccccc1)c1ccc(Cl)cc1-2
Yield: 28.4 %

Procedure:
2.1 g of 10-benzylidene-7-chloro-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one dissolved in 20 ml of a mixture of methanol and dimethylformamide (1/1 by volume) are hydrogenated at a temperature in the region of 20° C. and at a pressure of 9.6 bar of hydrogen for 24 hours in the presence of 10% palladium on charcoal. The catalyst is then filtered off under inert atmosphere and the solvents are evaporated off. The brown oil obtained is taken up in 25 ml of methanol and, after addition of 50 ml of distilled water, a pink precipitate forms. The solid thus obtained (1.3 g) is recrystallized in 150 ml of a mixture of methanol and water (1/2 by volume). 0.6 g of 10-benzyl-7-chloro-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained, in the form of a beige solid the melting point of which is greater than 260° C. (Analysis C20H14ClN3 O·0.41 H2O % calculated C: 69.07; H: 4.06; Cl: 10.19; N: 12.08; % found C: 69.0; H: 3.9; Cl: 10.5; N: 12.4).
Reaction SMILES: C([NH:8][C:9]1[C:29]2[CH2:28][CH2:27][CH2:26][C:25]=2[C:12]2[O:13][CH2:14][CH:15]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:11]=2[C:10]=1[CH3:30])C1C=CC=CC=1>CCCCCC.C(OCC)(=O)C>[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([CH:15]2[CH2:14][O:13][C:12]3[C:25]4[CH2:26][CH2:27][CH2:28][C:29]=4[C:9]([NH2:8])=[C:10]([CH3:30])[C:11]2=3)=[CH:21][CH:20]=1)([CH3:24])[CH3:23]
Reactant: Cc1c(NCc2ccccc2)c2c(c3c1C(c1ccc(C(C)C)cc1)CO3)CCC2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(N)c2c(c3c1C(c1ccc(C(C)C)cc1)CO3)CCC2
Yield: 91 %

Procedure:
Using N-benzyl-3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-5-amine synthesized in Reference Example 290, the title compound was synthesized in the same manner as in Reference Example 30. Yield 91%. Melting point: 112-113° C. (hexane-ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([C:25](O)=[O:26])=[C:17]2[CH3:28])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:30][CH2:31][C:32]1[C:33](=[O:41])[NH:34][C:35]([CH3:40])=[CH:36][C:37]=1[O:38][CH3:39].CN(C=O)C.CCN(C(C)C)C(C)C.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>O>[CH3:39][O:38][C:37]1[CH:36]=[C:35]([CH3:40])[NH:34][C:33](=[O:41])[C:32]=1[CH2:31][NH:30][C:25]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([CH:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[CH3:15])[C:17]=1[CH3:28])=[O:26]
Reactant: COc1cc(C)[nH]c(=O)c1CN
Reactant: Cc1c(C(=O)O)c2ccccc2n1C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc12
Temperature: 0 °C
Yield: 65.1 %

Procedure:
A 250 mL round bottom flask was charged with a magnetic stir bar, (R or S)-1-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-2-methyl-1H-indole-3-carboxylic acid (1.950 g, 5.05 mmol), 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(1H)-one hydrochloride (2.065 g, 10.09 mmol), DMF (25.2 ml, 5.05 mmol). Hunig's base (3.52 ml, 20.18 mmol). The reaction mixture was cooled to 0° C. and COMU (2.16 g, 5.05 mmol) was added. The reaction was allowed to stir overnight to room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extract was washed with brine, dried with MgSO4, filtered and conc. in vacuo to afford the crude material which was purified via silica gel chromatography (120 g) using MeOH/ethyl acetate (1:5) as eluent to afford the title compound (1.86 g, 3.29 mmol, 65.3% yield). LCMS 537 (M+1)+ 1H NMR (400 MHz, DMSO-d6) δ=11.83-11.71 (m, 1 H), 7.80 (br. s., 1 H), 7.73 (d, J=7.6 Hz, 1 H), 7.62 (d, J=7.8 Hz, 1 H), 7.06 (td, J=7.1, 14.4 Hz, 2 H), 6.21 (s, 1 H), 4.32 (br. s., 2 H), 4.16 (br. s., 1 H), 4.02 (br. s., 1 H), 3.85 (s, 3 H), 3.75 (br. s., 1 H), 2.70 (br. s., 1 H), 2.58 (s, 3 H), 2.37 (br. s., 1 H), 2.21 (s, 3 H), 1.90 (d, J=12.9 Hz, 1 H), 1.53 (d, J=6.9 Hz, 3 H), 1.35 (s, 10H), 1.21 (br. s., 1 H), 0.89 (d, J=8.7 Hz, 1 H), 0.67 (d, J=11.8 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([N+:13]([O-])=O)[CH:5]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:28]([N:35]1[C:39](=[O:40])[C:38](=[C:41]2[N:45]([CH3:46])[C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[S:42]2)[S:37][CH2+:36]1SC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([N:13]=[C:36]2[N:35]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:39](=[O:40])[C:38](=[C:41]3[N:45]([CH3:46])[C:44]4[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=4[S:42]3)[S:37]2)[CH:5]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(=O)OC)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4-ethylamino-3-nitrobenzoic acid methyl ester was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.73 (1H, dd), 7.65 (1H, d), 7.52 (1H, dd), 7.45–7.49 (2H, m), 7.27–7.38 (4H, m), 7.18 (1H, m), 7.06 (1H, d), 6.52 (1H, d), 5.19 (2H, s), 4.14 (1H, br t), 3.85 (3H, s), 3.78 (3H, s), 3.04 (2H, m), 1.04 (3H, t); MS(ESI): 531 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:10]([O:12][SiH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH3:11]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.O1CCCC1>[CH2:10]([O:12][Si:13]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH3:11]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCO[SiH](OCC)OCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: C1CCOC1
Product: CCO[Si](CCC(=O)OC(C)(C)C)(OCC)OCC
Yield: 1000.2 %

Procedure:
Into the 100 ml of dried tetrahydrofuran, were fed 25.8 g (20 mmol) of t-butyl acrylate and 32.8 g (20 mmol) of triethoxysilane, and the mixture was substituted by argon. To the mixture solution, 10 mg of chloroplatinic acid was added and the mixture was heated for 24 hours under reflux. After completion of the reaction, 58.5 g of the objective compound was obtained by removing solvent.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3].B.[OH-].[K+].[C:21](OC(=O)C)(=[O:23])[CH3:22]>FC(F)(F)C(O)=O.N1C=CC=CC=1.O>[C:21]([N:9]1[C:10]2[C:11](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH:7]([CH2:6][CH2:5][NH:4][C:2](=[O:3])[CH3:1])[CH2:8]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Agent: B
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(CCNC(C)=O)CN2C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution, cooled to 0° C., of melatonin (1 mmol) in trifluoroacetic acid (2 ml) is added dropwise borane (2 eq, 1M solution in THF). The mixture is stirred for 30 min at 0° C. followed by dropwise addition of water (1.5 ml), and the medium is left stirring for 1 h at room temperature. The mixture is then brought to pH=10 using 2N potassium hydroxide solution and is then extracted with dichloromethane. The crude product is separated on a column of flash silica (25/75/5 acetone/dichloromethane/methanol) and 110 mg of N-[2-(5-methoxyindolin-3-yl)ethyl]acetamide are obtained, which product is then acetylated with acetic anhydride in pyridine to give N-[2-(1-acetyl-5-methoxyindolin-3-yl)ethyl]acetamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]=[N+:18]=[N-:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(N=[N+]=[N-])C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methane sulfonate (930 mg, 3.70 mmol, Example 316) in dimethylformamide (20 mL), sodium azide (962 mg, 14.8 mmol, Aldrich) was added and the mixture was stirred at 90° C. overnight. The mixture was poured into water and extracted with ethyl acetate (5×10 mL) and the extracts were combined, washed with water, brine and dried with sodium sulfate. The solvent was removed to give a clear oil. 710 mg, 97%. The compound was directly used for the next step.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])[C@H:3]1[CH:17]=[CH:18][C@H:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:42]([NH2:44])[CH3:43]>C(Cl)Cl>[CH3:43][CH2:42][NH:44][C:14]([CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][C@@H:4]1[C@@H:3](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:2]([OH:1])[CH2:6][C@@H:5]1[OH:7])=[O:15]
Reactant: CCN
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](C=C[C@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: -10 °C
Reaction time: 2 h
Yield: 120.8 %

Procedure:
250 mL of methylene chloride were added to 12.3 g of (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenyl-pent-1-enyl)-cyclopentyl]-hept-5-enoic acid (compound (7), MW=402.54; 26.1 mmol; 1 equivalents). The solution is cooled to −10° C. At this temperature 5.1 g of triethylamine (MW=101.19; 50.4 mmol; 1.9 equivalents) and 5.1 g of ethyl chloroformate (MW=108.52; 48.1 mmol; 1.8 equivalents) were added and the mixture was stirred for two hours. A solution of 2.3 g of ethylamine (MW=45.08; 2.0 equivalents) in 10 mL methylenehloride was added. After stirring the reaction mixture for two hours at −10° C., the mixture was warmed to room temperature. The reaction was quenched by addition of 250 mL of water and the pH is adjusted to 2.0 with 1M aqueous hydrochloric acid. After separation of the layers, the organic layer was washed with 250 mL of saturated aqueous sodium bicarbonate, water and brine. After filtration the solution was concentrated under reduced pressure to give 13.1 g of bimatoprost crude (yield: 89%; as determined by NMR). Bimatoprost crude was purified as described below.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:11][CH3:12])([O:9][CH3:10])=[S:8].[C:14]([C:16]1[S:17][C:18]([CH3:22])=[CH:19][C:20]=1[OH:21])#[N:15]>CC(C)=O>[C:14]([C:16]1[S:17][C:18]([CH3:22])=[CH:19][C:20]=1[O:21][P:7]([O:11][CH3:12])([O:9][CH3:10])=[S:8])#[N:15]
Reactant: COP(=S)(Cl)OC
Reactant: Cc1cc(O)c(C#N)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COP(=S)(OC)Oc1cc(C)sc1C#N
Temperature: 20 °C
Reaction time: 15 h
Yield: 89.1 %

Procedure:
11.2 g of potassium carbonate and 12.8 g of O,O-dimethyl chlorothiophosphate were added to a solution of 11.2 g of 2-cyano-3-hydroxy-5-methyl-thiophene in 200 ml of acetone and the mixture was stirred for 15 hours at 20° C. and was then filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 7-3 cyclohexane-ethyl acetate mixture yielded 18.7 g of 2-cyano-3-(dimethoxythiophosphoryloxy)-5-methyl-thiophene with a refractive index of nD20 =1.539.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C@@H:10]([C:33]([O:35][CH3:36])=[O:34])[N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:12][CH:13]=2)=[CH:5][CH:4]=1>CO.[Pd]>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[CH2:13][CH2:12][NH:11][C@@H:10]2[C:33]([O:35][CH3:36])=[O:34])=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H]1C(c2ccc(C(F)(F)F)cc2)=CCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1NCC[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
(S)-Methyl 3-(4-(trifluoromethyl)phenyl)-1-trityl-2,5-dihydro-1H-pyrrole-2-carboxylate (0.22 g, 0.43 mmol) was stirred in MeOH (5.0 mL). Anhydrous HCl(g) was bubbled through the solution at 0° C. for 5 minutes. The mixture was stirred an additional 5 minutes at 0° C. and at room temperature for 10 minutes. The mixture was evaporated in vacuo. The residue was redissolved in MeOH (5.0 mL) and Pd/C (0.10 g, 0.05 mmol) was added. The resulting suspension was stirred under 1 atm H2 at room temperature overnight. The mixture was passed through a short path of Celite washing with MeOH (3×10 mL). The filtrate was evaporated in vacuo. The residue was dissolved in DCM/MeOH (10% with NH3) and adsorbed onto silica gel. The crude residue was purified by flash column chromatography (eluting with a gradient of pure DCM to 5% MeOH in DCM) to provide (2S,3S)-methyl 3-(4-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylate as a colorless oil (66 mg, 56%). LCMS (M+H) 274.2 calc. for C13H15F3NO2 274.1. 1H NMR (400 MHz, CDCl3): δ ppm 2.01-2.35 (m, 3H), 3.02-3.12 (m, 1H), 3.24 (s, 3H), 3.43-3.53 (m, 1H), 3.68 (q, J=8.22 Hz, 1H), 4.10 (d, J=8.61 Hz, 1H), 7.30 (d, J=8.02 Hz, 2H), 7.54 (d, J=8.02 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[CH2:12][C@H:11]([NH:13][C:14]3[N:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:10]2)[C:3]=1[NH2:24].[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[NH2:24][C:3]1[C:2]([C:32]2[CH:33]=[CH:34][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:30][CH:31]=2)=[N:7][CH:6]=[N:5][C:4]=1[NH:8][C@H:9]1[CH2:12][C@H:11]([NH:13][C:14]2[N:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Nc1c(Cl)ncnc1N[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
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: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ncnc(N[C@H]3C[C@H](Nc4ncc5ccccc5n4)C3)c2N)cc1
Temperature: 120 °C

Procedure:
6-chloro-N4-(trans-3-(quinazolin-2-ylamino)cyclobutyl)pyrimidine-4,5-diamine (from example 13 step 2, 0.045 g, 0.132 mmol), tetrakis(triphenylphosphine)palladium (0.015 g, 0.013 mmol), (4-methoxycarbonylphenyl)boronic acid (0.036 g, 0.197 mmol), and potassium carbonate (0.073 g, 0.527 mmol) were combined with dioxane (2 mL) and water (0.5 mL) and sealed in a vial under argon. The reaction was heated at 120° C. for 25 minutes in the microwave. The crude product was partitioned between water (100 mL) and ethyl acetate (100 mL) and the organic phase dried with magnesium sulfate. Purification using silica chromatography (0-8% (2N ammonia in methanol) in dichloromethane) gave the desired methyl 4-(5-amino-6-((trans-3-(quinazolin-2-ylamino)cyclobutyl)amino)pyrimidin-4-yl)benzoate (0.039 g, 0.088 mmol, 67.1% yield) as a yellow oil.