Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]([CH3:53])([C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:3][O:4][C@@H:5]1[C@@:12]2([CH3:37])[C@@H:13]3[CH2:14][CH2:15][C@H:16]4[C:25]([C@@:8]3([CH2:9][O:10][CH2:11]2)[CH2:7][C@H:6]1[N:38]1[C:42]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)=[N:41][CH:40]=[N:39]1)=[CH:24][CH2:23][C@:22]1([CH3:26])[C@:17]4([CH3:36])[CH2:18][CH2:19][C@@:20]([C@H:31]([CH3:35])[CH:32]([CH3:34])[CH3:33])([CH3:30])[C@H:21]1[C:27]([OH:29])=[O:28].C(N(CC)CC)C.ClC(Cl)(Cl)[C:63]([N:65]=C=O)=[O:64]>ClC(Cl)C>[NH2:65][C:63]([NH:1][C@:2]([CH3:53])([C:49]([CH3:50])([CH3:51])[CH3:52])[CH2:3][O:4][C@@H:5]1[C@@:12]2([CH3:37])[C@@H:13]3[CH2:14][CH2:15][C@H:16]4[C:25]([C@@:8]3([CH2:9][O:10][CH2:11]2)[CH2:7][C@H:6]1[N:38]1[C:42]([C:43]2[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=2)=[N:41][CH:40]=[N:39]1)=[CH:24][CH2:23][C@:22]1([CH3:26])[C@:17]4([CH3:36])[CH2:18][CH2:19][C@@:20]([C@H:31]([CH3:35])[CH:32]([CH3:34])[CH3:33])([CH3:30])[C@H:21]1[C:27]([OH:29])=[O:28])=[O:64]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(N)C(C)(C)C)[C@H](n4ncnc4-c4ccncc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(NC(N)=O)C(C)(C)C)[C@H](n4ncnc4-c4ccncc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a solution of (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (Example 173, 20 mg, 0.027 mmol) and triethylamine (0.015 mL, 0.11 mmol) in dichloroethane (0.27 mL) was added trichloroacetyl isocyanate (0.004 mL, 0.032 mmoL). The solution was stirred at room temperature for 70 min and then evaporated to dryness. Methanol (0.5 mL) was added to the residue followed by solid potassium carbonate (14.6 mg, 0.11 mmol and the mixture was stirred at room temperature. After 55 min, water (0.1 mL) was added giving a clear solution. The solution was stirred at room temperature for 1 hour and then stored at 5° C. for 64 hours. The solution was evaporated and the residue purified by reverse phase HPLC using a 19×150 mm Sunfire Preparative C18 OBD column (elution with MeCN/water+0.05% TFA). Fractions containing the product were evaporated and freeze-dried from a mixture of ethanol and benzene to give the title compound (not a salt form) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=2)[NH:31][C:30]=1[C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].[C:48](OC(=O)C)(=[O:50])[CH3:49]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:47])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:48](=[O:50])[CH3:49])[CH:36]=2)[NH:31][C:30]=1[C:39]1[CH:40]=[C:41]([CH3:46])[CH:42]=[C:43]([CH3:45])[CH:44]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:20])=[O:21])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc(N)c(S(C)(=O)=O)c3S(C)(=O)=O)C(=O)OC(C)(C)C)c2c1
Reaction time: 0.25 h

Procedure:
To a solution of {2-[5-amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}-[4-(4-amino(dimethanesulfonyl)phenyl)butyl] carbamic acid tert-butyl ester (from EXAMPLE 3.2 StepC, 60 mg in 3 mL dry methylene chloride) at 0° C. was added 0.025 mL pyridine followed by 0.020 mL acetic anhydride and the mixture stirred at low temperature. After 15 minutes, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed successively with a pH2 solution, saturated sodium bicarbonate and brine, then dried over sodium sulfate. Concentration in vacuo provided the crude title compound (65 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=O)[C:7]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:6]=2[O:5]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C(#N)C.C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:21])[C:7]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:6]=2[O:5]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2ccc([N+](=O)[O-])cc2C1=O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccc([N+](=O)[O-])cc2C1=S
Reaction time: 2 h
Yield: 173.5 %

Procedure:
To 2.0 g (0.007 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepin-5(4H)-one in 35 ml of acetonitrile was added 1.0 g (0.0023 mole) of phosphorus pentasulfide and the mixture heated to reflux for 2 hr. Another 0.4 g (0.001 mole) of phosphorus pentasulfide was added and heating continued for 2 hr. After cooling, the reaction mixture was diluted with 100 ml of toluene and filtered. The filtrate was washed with 3×50 ml of saturated sodium bicarbonate and 100 ml of water, dried over sodium sulfate, filtered, charcoaled, filtered, and concentrated by rotary evaporation. The crude oil was crystallized from isopropyl ether/toluene to give 1.2 g (57%) of yellow crystals, m.p. 153°-155° C.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[CH:9][CH:8]=1)C.[ClH:18]>>[ClH:18].[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:17])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)COc1ccc(NC(C)=O)cc1
Agent: Cl
Product: Nc1ccc(OCC(=O)O)cc1
Temperature: 10 °C
Yield: 77.6 %

Procedure:
A mixture (4-Acetylamino-phenoxy)-acetic acid ethyl ester 13 (375 g, 1.582 mmol), in concentrated hydrochloric acid (9.36 liters) was refluxed for 12 hours. Excess concentrated hydrochloric acid was distilled off in vacuum and filtered hot. The mixture was cooled to 10° C., filtered and dried to give pure 14 (250 g, 77.6%) as a wheat colored powder. The melting point was found to be 224-226° C. The structure was confirmed with NMR.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[N:19]=[C:18]([C:20]([O:22]C)=[O:21])[C:17]([NH2:24])=[C:16]([NH:25][C:26]4[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=4)[N:15]=3)=[CH:9][CH:8]=2)=[O:5])[CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1>[CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([S:13][C:14]3[N:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]([NH2:24])=[C:16]([NH:25][C:26]4[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=4)[N:15]=3)=[CH:11][CH:12]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1nc(Sc2ccc(NC(=O)C3CC3)cc2)nc(Nc2cc(C)[nH]n2)c1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(Sc3ccc(NC(=O)C4CC4)cc3)nc(C(=O)O)c2N)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 7 (45 mg, 0.1 mmol, 1 equiv) was dissolved in THF (1 mL). LiOH (1 mL, 0.4 N, 0.4 mmol, 4 equiv) was added to the solution. The mixture was stirred at room temperature for overnight, acidified to pH=5-6 with dilute HCl (1 N), concentrated under reduced pressure at room temperature, and dried under high vacuum for 48 hrs. to afford the crude product, which was used directly in the next step without further purification. A small sample was purified with reverse phase HPLC to afford the compound 8 as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:29][C:30]1[N:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1>>[NH2:36][C:34]1[N:35]=[C:30]([CH3:29])[C:31]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:32][CH:33]=1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: Cc1nc(N)ccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nc(N)ccc1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
2-(1-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (70 mg) was reacted with 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to produce 32.1 mg of 116 following reverse phase HPLC purification. MS (Q1) 478.3 (M)+
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)=[O:21])=[CH:15][CH:14]=1
Reactant: Clc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1
Yield: 86 %

Procedure:
To a 100 mL three-necked flask containing AlCl3 (4.797 g; 35.98 mmol) under N2, chlorobenzene (IVd) (36.6 mL; 359.76 mmol) was added in one portion at RT. To this suspension (4-bromo-phenyl)-acetyl chloride (IIIa) (7.0 g; 29.98 mmol) was added in one portion without cooling. Protocol and work-up was then similar with those described above. Title compound was obtained as a white powder (m=7.99 g) in a 86% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.Cl.Cl[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([NH:34][CH3:35])=[O:33])[CH:27]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:22][CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]([NH:34][CH3:35])=[O:33])[CH:27]=2)[C:5]([C:20]#[N:21])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: CNC(=O)c1cc(CCl)ccn1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.16 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-sulfanylpyridine-3,5-dicarbonitrile (Example 10A), 38.9 mg (0.18 mmol) of 4-(chloromethyl)-N-methylpyridine-2-carboxamide hydrochloride (Example 41A) and 53.8 mg (0.64 mmol) of sodium bicarbonate were dissolved in 1 ml of DMF and the mixture was stirred at RT overnight. 30 ml of water were added to the reaction mixture, and the precipitate was filtered off. The precipitate was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([O:11][CH3:12])[C:6]=2[C:5]([CH:13]2[C@H:18]([O:19]CC3C=CC=CC=3)[C@@H:17]([O:27]CC3C=CC=CC=3)[C@H:16]([O:35]CC3C=CC=CC=3)[C@@H:15]([CH2:43][O:44]CC3C=CC=CC=3)[O:14]2)=[CH:4][C:3]=1[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH3:61])=[CH:55][CH:54]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([O:11][CH3:12])[C:6]=2[C:5]([C@H:13]2[C@H:18]([OH:19])[C@@H:17]([OH:27])[C@H:16]([OH:35])[C@@H:15]([CH2:43][OH:44])[O:14]2)=[CH:4][C:3]=1[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH3:61])=[CH:55][CH:54]=1
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3OC)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)OCC3OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.8 %

Procedure:
To a solution of 7-chloro-6-(4-ethoxybenzyl)-3-methoxy-4-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran (124 mg, 0.147 mmol) in THF/MeOH (4 mL/2 mL) was added 10% Pd/C (12 mg) at rt. The reaction mixture was stirred at r.t. for 15 hours under hydrogen and filtered off. The filtrate was concentrated in vacuo and the residue was purified using reverse phase preparative HPLC to provide the title compound (38 mg, 54%) as a white solid.
Reaction SMILES: [H-].[Na+].C([Si]([S:13][Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C)(C)C.Br[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])[CH:31]=2)[CH:26]=1>O1CCCC1.C1(C)C=CC=CC=1.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:42][C:36]1[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=1[C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([SH:13])[CH:34]=[CH:33]2
Reactant: Fc1ccc(-c2ccc3cc(Br)ccc3c2)c(F)c1
Reactant: CC(C)[Si](S[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccc3cc(S)ccc3c2)c(F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.25 mmol) was added to a solution of triisopropylsilyl sulfide (1.2 mL, 5.59 mmol) in tetrahydrofuran (15 mL) at 0° C. The reaction was stirred at 0° C. for 5 minutes then at room temperature for 20 minutes. 2-Bromo-6-(2,4-difluorophenyl)naphthalene (Step 1, 1.63 g, 5.11 mmol) in toluene (30 mL) and tetrakis(triphenylphosphine)palladium(0) (310 mg) were added and the mixture degassed. The reaction was heated to reflux for 3 hours. The cooled reaction mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was suspended in isohexane and silica added. The mixture was filtered, washing the silica with isohexane. The filtrate was evaporated in vacuo and the residue dissolved in tetrahydrofuran (6 mL) and cooled to 0° C. A solution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 3 mL) was added and the reaction stirred at 0° C. for 30 minutes. Water was added then 2M hydrochloric acid. The reaction mixture was extracted with diethyl ether. The combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by filtration through a plug of silica, eluting with 10% dichloromethane/isohexane, to give 6-(2,4-difluorophenyl)-2-naphthyl hydrosulfide (0.78 g, contains some impurities). 1H NMR (500 MHz, CDCl3) δ 7.89 (1H, s), 7.77-7.74 (3H, m), 7.62-7.59 (1H, m), 7.52-7.46 (1H, m), 7.37 (1H, dd, J=1.8, 8.5 Hz), 7.01-6.93 (2H, m), 3.62 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([B:18]3[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]3)[C:13]=2[CH3:27])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C1N=CN([C:33](N2C=NC=C2)=[O:34])C=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:33](=[O:34])[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([B:18]4[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:26])([CH3:25])[O:19]4)[C:13]=3[CH3:27])[C:9](=[O:10])[CH:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NC(=O)Cc2ncccc2Cl)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2c(Cl)cccn2c1=O
Temperature: 110 °C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
A mixture of 2-(3-chloropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (0.192 g, 0.497 mmol) and CDI (0.322 g, 1.986 mmol) in toluene (2 mL) was heated at 110° C. After 5 h, the cooled mixture was diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to provide racemic 5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione as a bright yellow solid (0.133 g, 65% yield). Mass spectrum m/z 413 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.26 (dt, J=7.6, 0.9 Hz, 1H), 7.94 (dd, J=7.5, 1.3 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.27-7.18 (m, 2H), 6.36 (t, J=7.3 Hz, 1H), 6.31 (s, 1H), 1.57 (s, 3H), 1.36 (s, 12H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:33]=[N:34][C:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([C:47](O)=[O:48])[CH:45]=3)[C:40]([S:50]([CH3:52])=[O:51])=[CH:39]2)=[N:36][CH:37]=1.[CH3:53][NH:54][CH2:55][CH:56]([OH:58])[CH3:57]>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[N:36][C:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([C:47]([N:54]([CH2:55][CH:56]([OH:58])[CH3:57])[CH3:53])=[O:48])[CH:45]=3)[C:40]([S:50]([CH3:52])=[O:51])=[CH:39]2)=[N:34][CH:33]=1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Reactant: CNCC(C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(O)CN(C)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1

Procedure:
HATU coupling of 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid with 1-(methylamino)propan-2-ol. White solid. Yield: 0.16 g
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:16])[C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([CH:19]=[CH:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:11][CH:10]=1)[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(C=CC(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A mixture of N-tertiary-butyloxycarbonyl-N-methyl4-iodoaniline (11 g, Reference Example 9), tert-butyl acrylate (8.4 g), tris-(o-tolyl)phosphine (500 mg), palladium (II) acetate (150 mg), and triethylamine (7 g) in DMF (20 mL) was stirred at 90° C. under nitrogen overnight. The reaction mixture was cooled to room temperature then partitioned between ethyl acetate (500 mL) and hydrochloric acid solution (500 mL, 1M). The organic phase was dried and then evaporated. The residue was crystallised from cyclohexane to give the title compound (7.4 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33]Cl.Cl>C(#N)C.C(OCC)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ccc1Cl
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CN(C)CCOc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 32.7 %

Procedure:
To a solution of 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)benzamide from Example 51 (0.05 g) in acetonitrile (5 ml) was added potassium carbonate (0.065 g) and 2-dimethylaminoethyl chloride hydrochloride (0.037 g). The reaction mixture was stirred and heated at reflux temperature for 48 hours. The reaction mixture was evaporated under reduced pressure and residue dissolved in ethyl acetate and washed with brine. Drying over sodium sulphate (Na2SO4), followed by concentration under reduced pressure gave a residue which was subsequently purified by supercritical chromatography, eluting with CO2/methanol/0.1% diethylamine. Fractions containing product were concentrated under reduced pressure and the residue obtained was dissolved in diethyl ether. Hydrogen chloride (1 ml of a 1M solution in diethyl ether) was added dropwise and the resulting solid was triturated under diethyl ether and then dried in vacuo to leave the title compound as a white solid (0.020 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1.CI.[C:16](=O)([O-])O.[Na+]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH3:16])[C:11](=[O:13])[CH3:12])=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Sodium hydride (101.5 mg, 2.33 mmol) (55% in paraffin liquid) was added to a solution of 249 mg (1.16 mmol) of the title compound produced in step (i) of Reference Example 7 in N,N-dimethylformamide (2.5 ml), and the mixture was stirred at room temperature for 30 min. Thereafter, methyl iodide was added, and the mixture was stirred at room temperature for 1 hr. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 239 mg (yield 90%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C@@H:6]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:36](Br)[CH:37]=[CH2:38]>O1CCCC1>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:38][CH:37]=[CH2:36])[CH2:5][C@@H:6]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: C=CCBr
Reactant: COC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H](C[C@@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC
Temperature: -45 °C
Reaction time: 1 h

Procedure:
To a stirred, cold (−78° C.) solution of (2R)-2-benzyloxycarbonylamino-pentanedioic acid 1-tert-butyl ester 5-methyl ester (5.6 g, 15.9 mmol), prepared as described in J. Org. Chem., 55, 1711-1721 (1990) and J. Med. Chem., 39, 73-85 (1996), in 30 mL of tetrahydrofuran was added lithium bis(trimethylsilyl)amide (40 mL, 1 M in tetrahydrofuran, 39.8 mmol). The resulting mixture was stirred for 1 hour at −45° C. and then recooled to −78° C. Allyl bromide (5.2 mL, 63.7 mmol) was then added. After 2 hours the reaction was quenched by the addition of 1 M aqueous hydrogen chloride at −78° C. The mixture was then extracted with diethyl ether. The combined ethereal extracts were washed with brine and the mixture was dried over sodium sulfate. After filtration and concentration of the filtrate, the crude product was purified by silica gel chromatography (elution with 1:5 ethyl acetate/hexanes) to provide (2R,4R)-4-allyl-2-benzyloxycarbonylamino-pentanedioic acid 1-tert-butyl ester 5-methyl ester.