Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:5][C:4]=2[CH:3]=1.[CH3:18][C:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21](C(OC(C)(C)C)=O)[N:20]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:18][C:19]1[NH:20][N:21]=[CH:22][C:23]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:5][C:4]=2[CH:3]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=c1[nH]c(CN2CCCC2)nc2cc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1[nH]ncc1-c1cc2nc(CN3CCCC3)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 43.8 %

Procedure:
6-Bromo-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one (100 mg), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (294 mg), sodium carbonate (95 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (26 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 3 hr, 8M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at 100° C. for 30 min. After stirring, the mixture was extracted with ethyl acetate/tetrahydrofuran mixture, and the extract was dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate), and the obtained pale-yellow solid was crystallized from methanol/ethyl acetate to give the title compound (44 mg) as a pale-yellow solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:44]([N:51]1[CH2:55][C@H:54]2[C@H:56]([NH2:59])[CH2:57][CH2:58][C@H:53]2[CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl>[CH2:44]([N:51]1[CH2:55][C@H:54]2[C@H:56]([NH:59][C:8](=[O:10])[C@@H:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:57][CH2:58][C@H:53]2[CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(C)C[C@@H](C(=O)O)N1CCCS1(=O)=O
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCCS1(=O)=O
Reaction time: 0.25 h

Procedure:
(2S)-2-(1,1-Dioxidoisothiazolidin-2-yl)-4-methylpentanoic acid (359 mg, 1.526 mmol) was combined with triethylamine (0.387 mL, 2.77 mmol) in dichloromethane (10 mL). 1-Hydroxybenzotriazole (234 mg, 1.526 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.270 mL, 1.526 mmol) were added, and the reaction mixture was stirred for 15 minutes. Then (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (300 mg, 1.387 mmol) from Example 16 Step E was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with 10 mL of aqueous sodium bicarbonate and extracted with 3×20 mL of dichloromethane. The solvent was removed in vacuo. The crude material was applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS15-24) and eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.76 (d, J=6.9, 1H), 7.46-7.39 (m, 2H), 7.40-7.33 (m, 2H), 7.26 (dd, J=9.9, 17.2, 1H), 4.52 (t, J=7.7, 1H), 4.44-4.34 (m, 1H), 3.93 (dt, J=7.0, 14.5, 1H), 3.57 (dd, J=5.4, 13.1, 1H), 3.49-3.36 (m, 2H), 3.30-3.20 (m, 2H), 2.83-2.74 (m, 1H), 2.62-2.45 (m, 2H), 2.44-2.37 (m, 1H), 2.33-2.17 (m, 4H), 2.11 (qd, J=6.5, 12.5, 1H), 1.92-1.78 (m, 3H), 1.77-1.59 (m, 2H), 1.45-1.32 (m, 1H), 0.88 (d, J=6.6, 3H), 0.83 (dd, J=2.5, 6.5, 3H); MS (ESI+) m/z 434 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][C:9]([C:17]#[N:18])=[C:10]([N:12]=[CH:13][N:14](C)C)[CH:11]=1.[CH3:21][O:22][C:23](=[O:31])[CH2:24][C:25]1[CH:29]=[C:28](N)[NH:27][N:26]=1>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]2[C:9]([C:17]([NH:18][C:28]3[NH:27][N:26]=[C:25]([CH2:24][C:23]([O:22][CH3:21])=[O:31])[CH:29]=3)=[N:14][CH:13]=[N:12]2)=[CH:8][C:7]=1[O:19][CH3:20]
Reactant: COC(=O)Cc1cc(N)[nH]n1
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OCCCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1cc(Nc2ncnc3cc(OCCCCl)c(OC)cc23)[nH]n1
Yield: 72.9 %

Procedure:
N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (230 mg, 0.78 mmol) in acetic acid (0.7 ml) was heated with methyl(5-amino-1H-pyrazol-3-yl)acetate (110 mg, 0.74 mmol) at reflux for 1 hour. The mixture was cooled, the acetic acid was evaporated in vacuo, and the residue purified by chromatography on silica gel, eluting with methanol:ammonia:dichloromethane (9:1:90), to yield methyl (5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)acetate (219 mg, 69% yield) as a cream solid:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:34][C:35]1[CH:36]=[C:37]([C:45]2[O:49][N:48]=[C:47]([C:50]3[CH:51]=[CH:52][CH:53]=[C:54]4[C:58]=3[N:57]([CH3:59])[CH:56]=[C:55]4C=O)[N:46]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH:42]([CH3:44])[CH3:43]>CS(C)=O>[Cl:34][C:35]1[CH:36]=[C:37]([C:45]2[O:49][N:48]=[C:47]([C:50]3[CH:51]=[CH:52][CH:53]=[C:54]4[C:58]=3[N:57]([CH3:59])[CH:56]=[C:55]4/[CH:24]=[CH:4]/[O:3][CH3:2])[N:46]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH:42]([CH3:43])[CH3:44]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CO/C=C/c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Reaction time: 0.33 h

Procedure:
To a solution of (methoxymethyl)triphenylphosphonium chloride (2.9 g) in dimethyl sulfoxide (20 mL) stirred under nitrogen at 20° C. was added a solution of NaHMDS (8.6 mL, 1.0 mol/L in THF) dropwise during 5 mins. The reaction mixture was stirred at this temperature for 20 mins. Then 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D87) (1.4 g) was added in one portion. The mixture was stirred at room temperature for 30 mins. The reaction mixture was quenched with water, partitioned between ether (100 mL) and water (50 mL). The organic phase was washed with water and brine, dried over sodium sulphate and evaporated to afford 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-3-[(E)-2-(methyloxy)ethenyl]-1H-indole (D87) as a brown oil (3.8 g), used directly in the next step. MS (ES): C23H22ClN3O3 requires 423; found 424.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.P([O-])([O-])([O-])=O.N.C1CCCCC1>C(OCC)(=O)C.O>[CH:35]([C:5]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:2]([CH3:1])=[N:3][N:4]=1)([CH3:36])[CH3:37]
Reactant: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCCCC1
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
Crystalline form 1 of maraviroc phosphate (5 gm) was dissolved in ethyl acetate (60 ml) and water (40 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with ammonia solution (3 ml) and stirred for 15 minutes. The separated organic layer was dried with sodium sulfate and treated with carbon. The ethyl acetate was distilled off under vacuum at below 45° C. to obtain residual mass. To the residual mass was added cyclohexane (50 ml) and stirred for 15 minutes at room temperature, filtered. The solid obtained was dried to obtain 3.5 gm of maraviroc amorphous form.
Reaction SMILES: C[O:2]C1C=CC(C=CC(O)=O)=CC=1.[CH:14]1([N:20]=[C:21]=[N:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.NCCC[Si](OC)(OC)OC>>[CH:23]1([NH:22][C:21]([NH:20][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:2])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: CO[Si](CCCN)(OC)OC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
30 g of p-methoxycinnamic acid and 35.1 g of dicyclohexylcarbodiimide were added to a 1 L round 3-necked flask equipped with a dropping funnel and a cooler, 600 mL of toluene newly distilled from sodium ketyl was added thereto, and the resultant mixture was refluxed to yield a homogeneous solution. After about 30 minutes, 37.5 g of 3-aminopropyltrimethoxysilane was dropped over 30 minutes through the dropping funnel. The resultant reaction mixture was refluxed for 4 hours, and then toluene was removed by vacuum distillation without contacting with moisture. Dicyclohexyl urea formed in a remaining solution was removed by filtration to yield a product. The resultant product was determined using FT-IR and thin layer chromatography (TLC). Yield of the resultant product is about 40 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.Cl[C:15]1[C:19]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=2[S:17](=[O:26])(=[O:25])[N:16]=1.C(#N)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:15]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[S:17](=[O:25])(=[O:26])[N:16]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: O=S1(=O)N=C(Cl)c2cc(Cl)ccc21
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Cc1cc(Br)cnc1CCCCNC1=NS(=O)(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a refluxing solution of 4-(5-bromo-3-methyl-2-pyridinyl)butylamine (300 mg, 1.23 mmol) in chloroform (20 ml, purified as in previous example) was added over 10 minutes a solution of 3,5-dichloro-1,2-benzisothiazole 1,1-dioxide (U.S. Pat. No. 4,490,527) (400 mg, 1.69 mmol) in chloroform (20 ml)/acetonitrile (10 ml). Since a precipitate formed during the addition, another 10 ml of acetonitrile was added to give almost complete solution. Heating at 65°-70° C. was continued for 60 minutes giving a slightly cloudy mixture. Cooling to room temperature, filtration and evaporation of the filtrate in vacuo gave a solid residue. Recrystallization from methanol/methylene chloride/2-propanol gave 0.410 g of the title compound as an off-white solid hydrochloride: m.p. 231°-235° C., IR(KBr) 3005, 2500 (broad), 1620, 1278, 1160 cm-1. 1H NMR (Me2SO-d6) 9.87 (1H, t), 8.68 (1H, s), 8.60 (1H, s), 8.25 (1H, s), 7.90 (2H, m), 3.42 (2H, m), 2.83 (2H, m), 2.37 (3H, s), 1.68 (4H, m).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH:14]([CH3:18])[C:15]([CH3:17])=[CH2:16])[N:10]=[CH:9][N:8]=1)[C:2]#[C:3][CH2:4][CH3:5].[ClH:19].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)C>[CH2:1]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH:14]([CH3:18])[C:15]([Cl:19])([CH3:17])[CH3:16])[N:10]=[CH:9][N:8]=1)[C:2]#[C:3][CH2:4][CH3:5]
Reactant: Cl
Reactant: C=C(C)C(C)Oc1cc(OCC#CCC)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC#CCOc1cc(OC(C)C(C)(C)Cl)ncn1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution containing 0.3 g of 4-(2-pentynyloxy)-6-(1,2-dimethyl-2-propenyloxy)pyrimidine in 3 ml of tetrahydrofuran was added dropwise 3.66 ml of a 1 mol/l solution of hydrogen chloride in diethyl ether, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into a saturated aqueous sodium hydrogencarbonate solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium chloride, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.07 g of 4-(2-pentynyloxy)-6-(2-chloro-1,2-dimethylpropyloxy)pyrimidine (the present compound (41)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C@H:5]([N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:18])[CH3:6].Br[CH2:21][C:22]1[C:26]2[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=2[S:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C@H:5]([N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:21][C:22]2[C:26]3[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=3[S:24][N:23]=2)[C:8]1=[O:18])[CH3:6]
Reactant: COC(=O)C[C@@H](C)n1c(=O)[nH]c2ccccc2c1=O
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C[C@@H](C)n1c(=O)c2ccccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.6 %

Procedure:
(R)-3-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)-butyric acid methyl ester (124 mg, 0.5 mmol) (prepared according to example 4, steps 1-2), 3-bromomethyl-4,6-dimethyl-1,2-benzisothiazole (150 mg, 0.59 mmol) (prepared according to example 5, steps 1-6), and potassium carbonate (345.5 mg, 2.5 mmol) are combined in a reaction vial and DMF (1 mL) is added. The reaction mixture is agitated at ambient temperature for 18 hours then diluted with water (15 mL). The product is isolated by filtration and purified by flash chromatography using an ethyl acetate/hexane gradient to provide (R)-3-[1-(4,6-dimethyl-1,2-benzisothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-butyric acid methyl ester (196 mg, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([I:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([I:16])=[N:14][N:13]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][O:29]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1cc(Cl)nc2[nH]nc(I)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(Cl)nc2c1c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (14 g, 39.8 mmol) and p-toluenesulfonic acid monohydrate (0.75 g, 3.9 mmol) in anhydrous chloroform (200 ml) at 0° C. was added dropwise 3,4-dihydro-2H-pyran (5.45 ml, 59.7 mmol). The reaction mixture was allowed to warm to room temperature, stirred overnight and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using a stepwise gradient of ethyl acetate (0-20%) in cyclohexane to afford the title compound as a yellow solid (9.4 g, 54%). LC/MS (Method LC8): Rt=2.08 min; m/z=351 [M+H-THP]+.
Reaction SMILES: Br[C:2]1[S:6][N:5]=[CH:4][CH:3]=1.Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:46])([CH3:45])[CH2:15][C:16]2[N:17]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:18]=[C:19]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[N:20]=2)=[CH:10][CH:9]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:19]1[N:20]=[C:16]([CH2:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3[S:6][N:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)([OH:46])[CH3:45])[N:17]([C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:18]=1
Reactant: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(C)(O)c2ccc(Br)cc2)n1
Reactant: Brc1ccns1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(C)(O)c2ccc(-c3ccns3)cc2)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Palladium tetrakis(triphenylphosphine) (39 mg, 0.03 mmol) was added to a degassed, ambient temperature solution of 5-bromoisothiazole (55 mg, 0.34 mmol), 2-(4-bromophenyl)-1-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]propan-2-ol (200 mg, 0.34 mmol) and hexamethylditin (110 mg, 0.34 mmol) in 1,4-dioxane (15 mL). After stirring at 90° C. for 16 h, the reaction mixture was diluted with water and extracted with ethyl acetate and methylene chloride. The combined organic extracts were concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 1-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-2-(4-isothiazol-5-ylphenyl)propan-2-ol.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:22])[CH2:7][N:8]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:4].[CH3:23][O:24][CH2:25][CH2:26]Br.[ClH:28]>O1CCCC1.C(OCC)(=O)C>[ClH:28].[NH2:8][CH:7]([CH2:26][CH2:25][O:24][CH3:23])[C:6]([O:5][CH2:3][CH3:4])=[O:22]
Reactant: COCCBr
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N)CCOC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.8 g) is added to a solution of N-(diphenylmethylene)glycine ethyl ester in tetrahydrofuran under ice cooling, then the temperature is raised to room temperature, and the mixture is stirred for one hour. 2-Bromoethyl methyl ether (4.22 ml) is added to the mixture, and the whole is refluxed overnight. The reaction mixture is cooled to room temperature, 0.1 N hydrochloric acid is added thereto, and the whole is stirred for four hours. Ethyl acetate is added to the reaction mixture, and the whole is extracted with 0.1 N hydrochloric acid. The extract is basified with a saturated aqueous sodium hydrogencarbonate solution, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, a 4 N hydrogen chloride/ethyl acetate solution is added to the resulting residue, and the whole is concentrated under reduced pressure again to give the titled reference compound (2.67 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].[ClH:21].C1(C)C=CC=CC=1.CCO>CO.[OH-].[OH-].[Pd+2]>[ClH:21].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[CH2:7][NH2:8]
Reactant: Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: Cc1ccccc1
Product: Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Reaction time: 18 h
Yield: 99.1 %

Procedure:
Intermediate (4t) (1.13 g, 4.23 mmol; prepared as in Example 94, Steps A-C) was dissolved in methanol (50 mL) and 20% palladium hydroxide on activated carbon (0.50 g, 0.71 mmol) was added to the solution under nitrogen atmosphere. After the addition of concentrated HCl (12 N, 5.0 mL, 60 mmol), the mixture was stirred under hydrogen atmosphere overnight (18 hours). The mixture was filtered and palladium hydroxide was washed with MeOH. After evaporation, the crude residue was azeotroped with a mixture of toluene and EtOH to dryness to compound (5t) as a white powder (1.29 g, 99% yield) 1HNMR (400 MHz, CDCl3) δ 8.72 (br, 3H), 8.01 (s, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.57 (dd, J=9.4, 2.3 Hz, 1H), 7.38 (s, 1H), 7.19 (d, J=3.1 Hz, 1H), 7.04 (td, J=74.8, 3.1 Hz, 1H), 7.02 (dd, J=195.1, 4.7 Hz, 1H), 4.07 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12].C([O-])(O)=O.[Na+]>ClCCl>[OH:12][CH2:11][CH2:13][NH:14][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8]
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(NCCO)c1ccc(Br)s1
Yield: 65.2 %

Procedure:
A mixture of 5-bromo-thiophene-2-sulfonyl chloride (1.5 g, 4. mmol) and ethanolamine (0.72 mL, 12 mmol) in dichloromethane (8mL)/sat. NaHCO3 solution (8 mL) was stirred at 20° C. for 28 h. The mixture was partitioned between AcOEt (50 mL) and H2O (150 mL). The organic layer was dried (Na2SO4) and evaporated to give the title compound (1.07 g, 93%) as a pale-yellow oil. MS (ISP) 284.0 [(M−H)−].
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH:27]([F:29])[F:28])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.[Si]([O:39][CH2:40][CH:41]=O)(C(C)(C)C)(C)C.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.O>C(Cl)Cl>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:30][CH3:31])=[C:7]([CH:5]4[CH2:6][N:3]([CH2:41][CH2:40][OH:39])[CH2:4]4)[C:12]([F:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH:27]([F:29])[F:28])[C:20]=12
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(CCO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.9 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (45 mg, 0.090 mmol), {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (110 mg, 0.63 mmol) and triethylamine (63 μL, 0.45 mmol) in methylene chloride (0.9 mL) was added sodium triacetoxyborohydride resin (0.12 g, 0.27 mmol). The mixture was stirred at room temperature for 2 h, then filtered. The filtrate was treated with 6.0 M hydrogen chloride in water (0.2 mL, 0.9 mmol), and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.5 mg, 5.6%). LCMS calculated for C20H23ClF3N6O2 (M+H)+: m/z=471.1; Found: 471.2. The racemic product was separated on a Phenomenex Lux Cellulose-4 column, eluting with 20% ethanol in hexanes, at flow rate of 18 mL/min, and column loading of ˜4 mg/injection to separate two enantiomers. First peak retention time 13.1 min; second peak retention time 16.3 min.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10](C=O)=[CH:9][CH:8]=1)[CH3:2].[CH2:26]([NH:28][CH:29]=[O:30])[CH3:27].[CH:31](O)=O.[OH-].[Na+]>O>[CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:31][N:28]([CH2:26][CH3:27])[CH:29]=[O:30])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN(CC)CCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Reactant: CCNC=O
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(C=O)Cc1ccc(NCCN(CC)CC)c2c(=O)c3ccccc3sc12
Yield: 57 %

Procedure:
A solution of 2.0 g (5.6 mmol) of 1-[[2-(diethylamino)ethyl]amino]-9-oxo-thioxanthen-4-carboxaldehyde, N-ethylformamide (24.0 mL) and formic acid (3.0 mL, 79.5 mmol) was heated at 170° C. for 4 hours. The reaction mixture was cooled, poured into water and made basic with 10% sodium hydroxide. A solid was obtained which was collected by filtration and washed with water. The solid residue was taken up in chloroform/water, and the organic layer was separated and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by radial chromatography eluting with isopropylamine/methanol/ethyl acetate (0.5/1/98.5) to afford 1.32 g (57%) of the N-ethylformamide as an orange solid, m.p.75°-77° C.