Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])[CH3:8].[C:24]([O:32][C@@H:33]1[CH2:41][C@@H:36]2[O:37][C:38](=[O:40])[CH2:39][C@@H:35]2[C@H:34]1/[CH:42]=[CH:43]/[C@H:44]([C:46]1[S:50][C:49]2[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=2[CH:47]=1)[OH:45])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[C:24]([O:32][C@@H:33]1[CH2:41][C@@H:36]2[O:37][C:38](=[O:40])[CH2:39][C@@H:35]2[C@H:34]1/[CH:42]=[CH:43]/[C@H:44]([C:46]1[S:50][C:49]2[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=2[CH:47]=1)[O:45][Si:10]([C:7]([CH3:9])([CH3:8])[CH3:6])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](O[C@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)c1cc2ccccc2s1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
A stirring mixture consisting of (3aR,4R,5R,6aS)-4-((R,E)-3-(benzo[b]thiophen-2-yl)-3-hydroxyprop-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (5a, limiting reagent) and imidazole (1.1 molar equivalents) in DMF (5 M in 5a) is cooled to 0° C. under a nitrogen atmosphere. A solution consisting of TBDPSCl (1.1 molar equivalents) in DMF is added slowly. Upon completion of the reaction, as judged by TLC, the reaction mixture is diluted with ethyl acetate and is washed with water and brine. The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate to afford the title intermediate 6a.
Reaction SMILES: OO.C(O)=[O:4].[O:6]1[C:17]2[C:9](=[CH:10][C:11](=[CH:15][CH:16]=2)[CH:12]=[CH:13][CH3:14])[O:8][CH2:7]1.S(=O)(=O)(O)O>O.CC(C)=O>[CH2:7]1[O:6][C:17]2[CH:16]=[CH:15][C:11]([CH2:12][C:13](=[O:4])[CH3:14])=[CH:10][C:9]=2[O:8]1
Reactant: CC=Cc1ccc2c(c1)OCO2
Reactant: O=CO
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Cc1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
Hydrogen peroxide (70 ml, 30%) was added with caution to a solution of formic acid (350 ml, 88%) in a three-necked flask (1 L) cooled with running water. Isosafrole (72 ml) was added drop-wise, by a dropping funnel, to the reaction mixture at a rate to keep the temperature of the reaction mixture below 35° C. After the complete addition of isosafrole, a non-homogeneous solution was obtained. At this point, acetone (200 ml) was added to the reaction mixture at a rate to keep the temperature below 35° C. The reaction was allowed to stand at room temperature overnight. The solvent was removed by a rotary evaporator equipped with a dry-ice acetone cold trap, a high vacuum pump and a water bath with temperature not exceeding 30° C. Ethyl ether (500 ml) was added to the residue. The solution was transferred into a separatory funnel. The organic phase was washed with sodium bicarbonate (0.1 N, 2×500 ml) and water (3×300 ml). The organic phase was transferred into a round bottom flask. The solvent was removed by rotary evaporation. Concentrated sulfuric acid (75 ml) was diluted drop-wise in water (425 ml). Methanol (160 ml) was added to the oily residue, and mixed to obtain a homogeneous solution. The sulfuric acid solution was added to the methanolic reaction mixture. The flask was equipped with a water-cooled reflux condenser and a heating mantel. The reaction mixture was heated to reflux for 4 hours. The heat was removed and crushed ice (150 g) was added to the reaction mixture. The reaction mixture was transferred into a separatory funnel and extracted with ethyl ether (1×350 ml, 1×150 ml and 1×100 ml). The combined organic layers were washed with water (3×150 ml). Sodium hydroxide (40 ml, 0.1 N) was diluted in water (360 ml). The organic phase was washed with diluted sodium hydroxide (2×200 ml, 10 mM) and saturated sodium chloride solution (100 ml). The organic layer was dried with anhydrous sodium sulfate (20 g) overnight. The drying agent was filtered and the cake was washed with ethyl ether (2×10 ml). The solvent was removed by rotary evaporation. The product was distilled at reduced pressure (2-0.5 mmHg). The second fraction distilling at 90-100° C. (˜1 mmHg) contained product. The product was identified by El/MS with the m/z of 182. Infrared spectrum (cm−1) indicated 1714 (C═O) and 2898 (C—H) stretches corresponding to the product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]([CH2:17]C(O)=O)[CH2:13][C:14](O)=O)[C:6]2=[O:11].[NH2:21][C:22](N)=[O:23].CN(C)C=[O:28]>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:13][CH2:14][C:22](=[O:23])[NH:21][C:17]1=[O:28])[C:6]2=[O:11]
Reactant: NC(N)=O
Reactant: CN(C)C=O
Reactant: Nc1cccc2c1CN(C(CC(=O)O)CC(=O)O)C2=O
Product: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Yield: 30 %

Procedure:
A mixture of 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutaric acid (5 g) and urea (1.08 g) in N,N-dimethylformamide (25 ml) was stirred and heated under reflux for 3˜4 hours. The reaction mixture concentrated under reduced pressure at 60° C. and then was added into ice water by being stirred rapidly. After filter, the cake was washed with isopropanol. The crude product was recrystallized from isopropanol and active carbon to give 1.4 g of off-white target compound. Yield: 30%. mp: 252.1˜254.3° C.
Reaction SMILES: C1COCC1.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[C:17]([F:25])[C:16]=2[F:26])=[C:11]([F:27])[C:10]=1[F:28])[CH3:7].C([Li])CCC.[CH2:34]([C@H:37]1[CH2:42][CH2:41][C@H:40]([CH:43]2[CH2:46][CH2:45]O2)[CH2:39][CH2:38]1)[CH2:35][CH3:36]>C(O)=O>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:36][CH2:35][CH:34]([CH:37]4[CH2:38][CH2:39][CH:40]([CH2:43][CH2:46][CH3:45])[CH2:41][CH2:42]4)[O:23][C:22]3=[O:24])=[C:17]([F:25])[C:16]=2[F:26])=[C:11]([F:27])[C:10]=1[F:28])[CH3:7]
Reactant: CCC[C@H]1CC[C@H](C2CCO2)CC1
Reactant: CCOc1ccc(-c2ccc(CC(=O)O)c(F)c2F)c(F)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O=CO
Product: CCCC1CCC(C2CCC(c3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)C(=O)O2)CC1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
THF (50 ml) was added to 2-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)acetic acid (10) (2.0 g) prepared in the eighth step. The solution was cooled to −5° C., and n-butyllithium (1.59 M in n-hexane; 7.66 ml) was added dropwise. After the addition had been completed, the reaction mixture was returned to room temperature, and the stirring was continued for 30 minutes. The solution was then cooled to −65° C., and 2-(trans-4-propyl-cyclohexyl)-oxetane (5) (1.0 g) in a THF (5 ml) solution and a boron trifluoride-diethyl ether complex (0.86 g) were added dropwise. After the addition had been completed, the reaction mixture was returned to room temperature, and a 10% aqueous solution of formic acid (100 ml) was added to give two layers. The water layer was extracted with toluene (20 ml) three times and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 200 g, eluent: heptane/ethyl acetate=90/10 by volume) to give 3-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)-6-(4-propylcyclohexyl)tetrahydropyran-2-one (11) (2.35 g) in 86.1% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:17]=1)[N:5]=2.[C:26](Cl)(=[O:28])[CH3:27]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(OCC)(=O)C.O>[C:26]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23])[CH:17]=1)[N:5]=2)(=[O:28])[CH3:27]
Reactant: Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
N-{5-[(2-Amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-chlorophenyl}-2,2,2-trifluoroacetamide (1.8 g, 4.63 mmol) and N,N-dimethylpyridine-4-amine (566 mg, 4.63 mmol) were dissolved in pyridine (9.25 mL), acetyl chloride (0.658 mL, 9.25 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate (80 mL)/water (50 mL), and the organic layer was collected, and washed with saturated brine (50 mL). The mixture was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residual solid was crystallized from toluene/diisopropyl ether (1:3), collected by filtration, and dried to give the title compound (1.69 g, 85%) as a pale-yellow solid.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH2:30][CH2:29][CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH:33]=1
Reactant: ClCCCOc1cccnc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCOc3cccnc3)cc12

Procedure:
6-[3-(Pyridin-3-yloxy)-propoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime was prepared in 9% overall yield using the method described in example 147, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 3-(3-Chloro-propoxy)-pyridine.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].[F:7][C:8]([F:36])([F:35])[C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=1)[CH2:12][NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[C:25](F)[CH:24]=[CH:23][C:22]=2[N+:28]([O-:30])=[O:29])[CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[F:7][C:8]([F:36])([F:35])[C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=1)[CH2:12][NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[C:25]([O:4][CH:2]([CH3:3])[CH3:1])[CH:24]=[CH:23][C:22]=2[N+:28]([O-:30])=[O:29])[CH:16]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of propan-2-ol (2 mL) in N,N-dimethylformamide (5 mL), sodium hydride (72 mg, 3.00 mmol, 5.00 equiv), and N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide 14d (250 mg, 0.58 mmol, 1.00 equiv, 98%). The resulting solution was stirred for 3 h at 60° C. in an oil bath. The resulting solution was diluted with 200 mL of ethyl acetate and washed with 3×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 280 mg (99%) of product as a brown oil.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.O>CN(C)C=O>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4](=[O:11])[O:3][C:2]2=[O:12])=[CH:18][CH:17]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Commercially available 2H-3,1-benzoxazine-2,4(1H)-dione (1.0 g, 1.0 eq)) was taken up in N,N-dimethylformamide (15 ml) then treated with portion wise addition of sodium hydride (60% oil dispersion, 0.26 g, 1.05 eq). After stirring 30 minutes, p-fluorobenzyl bromide (1.22 g, 1.05 eq) was dripped in over 5 minutes. The reaction stirred at room temperature for 1 hour. A slurry of yellow solid resulted. Water (15 ml) was added to aid filtration. The solid was collected and recrystallized from ethyl acetate and hexanes (1:3) to afford 1.2 g (73%) of a brown crystalline solid. 1H-NMR (DMSO-d6): δ 8.0-7.9 (m, 1H), 7.8 (t, J=8.7 Hz, 1H), 7.5 (dd, J=8.7, 5.4 Hz, 2H), 7.3-7.0 (m, 4H), 5.3 (s, 2H); LC/MS calc M+Na 294, obs M+Na 294.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[N:16][N:15]=2)[CH:10]=[CH:11][CH:12]=[O:13])=[CH:4][CH:3]=1.[C:28]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:29][C:30]([CH3:32])=[O:31]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[N:16][N:15]=2)[CH:10]=[CH:11][CH:12]([OH:13])[CH2:32][C:30](=[O:31])[CH2:29][C:28]([O:34][CH2:35][CH3:36])=[O:33])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CCn1nnnc1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1CC
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.5 g (1.4 mmoles) of 5,5-bis(4-fluorophenyl)-4-(1-ethyl-1H-tetrazol-5-yl)2,4-pentadienal in tetrahydrofuran at -50° C., was added 1.75 mL of 0.8M (1.4 mmoles) of a freshly prepared solution of ethyl acetoacetate dianion [described in Example 10]. The solution was stirred for 30 minutes at -50° C. and then allowed to warm to -10° C. during the next 30 minutes. The solution was quenched with 1N HCl and extracted with methylene chloride. The organic extracts were dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with chloroform to give 0.4 g of the title compound as an oil. MS (CI): m/e=497 for (M+H)+ ;
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.ClC1[N:20]=[CH:19]C(F)=CC=1C(O)=O>>[Cl:1][C:2]1[C:3]([CH2:4][C:19]#[N:20])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=C(O)c1cc(F)cnc1Cl
Product: N#CCc1cccnc1Cl

Procedure:
(2-Chloropyridin-3-yl)acetonitrile was synthesized analogous to intermediate 13 using 2-chloronicotinic acid as a starting material in place of 2-chloro-5-fluoronicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C@@H:9]1[CH2:11][C@H:10]1[CH:12]([NH:14][O:15][CH3:16])[CH3:13].C(N(CC)CC)C.[F:24][CH:25]([F:35])[C:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][N:28]([CH3:34])[N:27]=1>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C@@H:9]1[CH2:11][C@H:10]1[CH:12]([N:14]([O:15][CH3:16])[C:31]([C:30]1[C:26]([CH:25]([F:35])[F:24])=[N:27][N:28]([CH3:34])[CH:29]=1)=[O:32])[CH3:13]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)[C@@H]1C[C@H]1c1c(F)cccc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)[C@@H]1C[C@H]1c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a stirred solution of trans N-{1-[2-(2-Chloro-6-fluoro-phenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine (0.80 g; 3.3 mmol) prepared as described in example P14 and triethylamine (0.60 ml; 4.3 mmol) in dichloromethane (10 ml) at ambient temperature was added dropwise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.64 g; 3.3 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (60 ml) and extracted with dichloromethane (3×25 ml). Combined organic layers were washed with water (10 ml), brine and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 1:99) to afford 1.30 g (100% of theory) of trans 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid {1-[2-(2-chloro-6-fluoro-phenyl)-cyclopropyl]-ethyl}-methoxy-amide as a clear viscous oil.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](Cl)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:18][NH2:19]>C(N(CC)CC)C.C(O)CO.O>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:18][NH2:19])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=S(=O)(c1ccccc1)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: OCCO
Solvent: O
Product: NNc1ccc(S(=O)(=O)c2ccccc2)cc1

Procedure:
A mixture of 4-chlorophenyl phenyl sulfone (10.1 g, 40.0 mmol), hydrazine monohydrate (30 mL), and triethylamine (4 drops) in ethylene glycol (20 mL) is heated at 150° for 15 hr. Upon cooling, the mixture is diluted with H2O and filtered. The residual solid is washed with H2O until the washings are neural (pH=6). This material is then triturated with methylene chloride and dried under reduced pressure at 50° to give the title compound, IR (drift) 3282, 1586, 1514, 1306, 1291, 1158, 1145, 1104, 996, 813, 756, 730, 717, 688 and 678 cm−1; NMR (300 MHz, CDCl3) 7.70–7.85, 7.45–7.65, 6.79 and 4.22 δ; MS (EI) m/z 248 (M+), 125, 123, 108, 107, 90, 80, 77, 63 and 51.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[N:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[N:24]=[CH:25][C:20]([Cl:19])=[CH:21][N:22]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncc(Cl)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-chloro-pyrimidine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=400.0 [M+H]+.
Reaction SMILES: C(C(CC)CNCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:37]([C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)=O.[CH3:47][C@H:48]([NH2:53])[C:49]([CH3:52])([CH3:51])[CH3:50].[BH3-]C#N.[Na+]>>[CH3:47][C@H:48]([NH:53][CH2:37][C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)[C:49]([CH3:52])([CH3:51])[CH3:50]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: C[C@H](N)C(C)(C)C
Agent: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NCc1ccc(B(O)O)s1)C(C)(C)C
Yield: 38.9 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [(1S)-1,2,2-trimethylpropyl]amine (32 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[(1S)-1,2,2-trimethylpropyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(1S)-1,2,2-trimethylpropyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol) to give 10.3 mg of the title compound (12%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[NH4+].[NH2:15][C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:30]=[CH:29][C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=2)[N:20]=1.O>CC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:13][C:12]([NH:15][C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[N:20]=2)=[S:11])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1nc(-c2ccc3c(c2)CCCC3)cs1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1nc(-c2ccc3c(c2)CCCC3)cs1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
4-Chlorobenzoyl chloride (911 mg) was added to a solution of ammonium thiocyanate (460 mg) in acetone (20 ml), and the solution mixture was heated over a water bath for 1 minute and stirred at room temperature for 1 hour. A solution of 2-amino-4-(5,6,7,8-tetrahydro-2-naphthyl)thiazole (1.0 g) in acetone (10 ml) was added to the solution, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into water, and the crystals which separated out were recovered by filtration and washed with water and hexane, successively. Recrystallization from dichloromethane-ethanol produced 1-(4-chlorobenzoyl)-3-[4-(5,6,7,8-tetrahydro-2-naphthyl-)2-thiazolyl]thiourea (Yield of 1.08 g, 58.1%) %) in the form of colorless needles. m.p. 193° to 194° C.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].Cl[O:10]C(C)(C)C.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[N:17]=1.O>C(#N)C.[Ag]=O.[Os](=O)(=O)(=O)=O>[Br:15][C:16]1[N:17]=[C:18]([C@@H:22]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@H:23]([OH:10])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(/C=C/c2cccc(Br)n2)c1
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(C)(C)OCl
Agent: O=[Ag]
Agent: O=[Os](=O)(=O)=O
Solvent: CC#N
Solvent: O
Product: COc1cccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)c2cccc(Br)n2)c1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl carbamate (109 mg, 0.931 mmol) in acetonitrile (5 mL) at 0° C. was added tert-butyl hypochlorite (0.105 mL, 0.93 mmol). After stirring for 5 min, the reaction was treated with silver oxide (108 mg, 0.465 mmol). After stirring for 10 min, the resulting suspension was treated with (E)-2-bromo-6-(3-methoxystyryl)pyridine (180 mg, 0.620 mmol), osmium tetroxide (0.1 mL, 0.32 mmol), and water (0.025 mL, 1.37 mmol). The ice bath was removed and stirring continued for 8 h. The reaction was filtered and treated with a solution of sodium sulfite (5% in water, 1.5 mL). The resulting solution was heated to 50° C. and held there for 8 h. The reaction was cooled to room temperature and diluted with ethyl acetate. The organics were washed with water, then brine, dried over magnesium sulfate, concentrated, and purified by column chromatography (25% EtOAc/Hex). HNMR of the purified material suggested that it was ca. 1:1 mixture of regioisomers. The product (114 mg, 43%) was used as a mixture of regioisomers. Mass spec.: 423.09 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[C:10](Cl)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:26]([CH3:28])[CH3:27]>CS(C)=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[C:10]([N:26]([CH3:28])[CH3:27])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(-c2ccccc2F)cc1[N+](=O)[O-]
Reactant: CNC
Solvent: CS(C)=O
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1-c1ccccc1F

Procedure:
The title compound was prepared from (2-chloro-2′-fluoro-5-nitro-biphenyl-4-yl)-carbamic acid tert-butyl ester (Example D1) (9.568 g, ca. 26 mmol) and Me2NH (60% in H2O, 12 mL) in DMSO (87 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (4.54 g).