Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][CH2:30][NH:31][CH3:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][CH2:30][NH:31][CH3:32])=[CH:4][CH:3]=1
Reactant: CCOc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CNCCCl
Product: CCOc1ccccc1N1CCN(C(=O)c2cn(CCNC)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) (2-chloro-ethyl)-methyl-amine gave the title compound.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:31]=[C:32]([Cl:34])[CH:33]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:38]2[CH2:37][CH2:36][N:35]([C:30]3[CH:29]=[C:28]([Cl:27])[CH:33]=[C:32]([Cl:34])[CH:31]=3)[CH2:40][CH2:39]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)c(Oc2ccccc2)nc1C
Yield: 82 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[NH2:34][C@@H:35]([CH3:45])[CH2:36][CH2:37][NH:38][CH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1.C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:4])[N:34]4[C@@H:35]([CH3:45])[CH2:36][CH2:37][N:38]([CH:39]5[CH2:44][CH2:43][S:42][CH2:41][CH2:40]5)[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: C[C@H](N)CCNC1CCSCC1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H]1CCN(C2CCSCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Yield: 49.2 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (25 mg, 0.055 mmol) and free based [(3S)-3-aminobutyl]tetrahydro-2H-thiopyran-4-ylamine (48 mg, 0.26 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (16 mg, 49%) as a film. This material was debenzylated in a second step in a manner similar to Z-26 to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (8 mg, 59%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.30 (d, J=7.2 Hz, 3H), 1.53-1.58 (m, 1H), 1.72-2.10 (m, 5H), 2.56-2.76 (m, 5H), 2.84-2.87 (m, 2H), 4.18 (dd, J=2.8, 14.0 Hz, 1H), 4.26 (dd, J=3.4, 14.2 Hz, 1H), 4.92-4.97 (m, 1H), 6.96-7.00 (m, 2H), 7.29-7.36 (m, 2H), 8.31 (s, 1H), 10.48 (m, 1H), 12.48 (br, 1H); ES+ MS: 501 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31].FC1(F)CCNC1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][Cl:31])[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: Cl
Agent: FC1(F)CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CCCCl)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 20.9 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]-triazin-4-ylamine (50 mg, 0.108 mmol), 3,3-difluoropyrrolidine hydrochloride (78 mg, 0.54 mmol, 5.0 eq), triethylamine (77 mg, 0.76 mmol, 7.0 eq), and sodium iodide (3.3 mg, 0.022 mmol, 0.2 eq) in anhydrous DMF (1.0 mL) was stirred at 50° C. for 6 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with 50% aq. brine (3×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in MeOH (3 mL) and purified using HPLC (RT=10.16 min) to give a colorless oil. Crystallization from DCM/hexane afforded 9.4 mg (20.8%) of the byproduct as a white solid. 1H-NMR (CD3OD) 8.35 (s, 1H), 7.82 (s, 1H), 7.81 (d, 1H), 7.64 (s, 1H), 7.36 to 7.30 (m, 5H), 7.23 (d, 1H), 6.62 (s, 1H), 5.66 (s, 2H), 3.64 (t, 2H), 3.14 (t, 2H), 226 to 2.22 (m, 2H); LC-MS [M+H]+=417/419, RT=2.91 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[S:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:18][CH2:19][CH2:20][N:21]1[C:25]([CH3:27])([CH3:26])[C:24](=[O:28])[NH:23][C:22]1=[O:29].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([C:9]2[S:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[N:4][C:5]([NH:18][CH2:19][CH2:20][N:21]2[C:25]([CH3:26])([CH3:27])[C:24](=[O:28])[NH:23][C:22]2=[O:29])=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: Clc1ncc(Br)c(-c2cc3ccncc3s2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3ccncc3s2)n1
Temperature: 170 °C

Procedure:
2-(5-Bromo-2-chloropyrimidin-4-yl)thieno[2,3-c]pyridine (0.38 g, 1.16 mmol), 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione (0.393 g, 2.3 mmol), diisopropylethyl-amine (0.4 mL, 2.3 mmol) and isopropyl alcohol (2 mL) were all placed in a microwave tube and heated to 170° C. for 20 min. The volatiles were removed in vacuo and the residue dissolved in 9:1 mixture of dichloromethane, preadsorbed onto silica gel and purified by flash chromatography using a gradient of 0 to 10% methanol in dichloromethane to obtain a yellow solid. Yield=0.4 g. MS (M+H)+ 461/463.
Reaction SMILES: [OH:1][C:2]1([C:9]([OH:11])=[O:10])[CH2:7][CH:6]2[CH2:8][CH:3]1[CH:4]=[CH:5]2.[H][H]>C(OCC)(=O)C.[C].[Pd]>[OH:1][C:2]1([C:9]([OH:11])=[O:10])[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2
Reactant: O=C(O)C1(O)CC2C=CC1C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C1(O)CC2CCC1C2
Yield: 143.1 %

Procedure:
In 100 ml of ethyl acetate, 10.0 g of the 2-hydroxy-5-norbornene-2-carboxylic acid of Formula (4a) obtained in Step b. was dissolved. To the resulting solution, 0.5 g of 10% palladium carbon was further added as a catalyst for catalytic hydrogenation. This solution was stirred for 2 hours in an atmosphere of hydrogen gas to carry out catalytic hydrogenation. After the reaction was completed, the catalyst was separated by filtration and the ethyl acetate was evaporated from the filtrate under reduced pressure to obtain 14.5 g of crude 2-hydroxynorbornane-2-carboxylic acid of Formula (5a).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[CH2:13]2)=[CH:6][C:7]=1[Br:24]
Reactant: CN1C(=O)CC(c2ccc(N)cc2)CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN1C(=O)CC(c2ccc(N)c(Br)c2)CC1=O
Yield: 67 %

Procedure:
A solution of 289 mg (1.32 mmol) of 4-(4-amino-phenyl)-1-methyl-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (15 mL) was treated portionwise with 224 mg (1.29 mmol) of solid NBS for 20 min. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (2×30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with 25-50% EtOAc-hexane afforded 265 mg (67%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C12H13N2O2Br, 297.0/299.0 (M+H), found 297.0/299.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:27](I)([CH3:29])[CH3:28].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH:27]([CH3:29])[CH3:28])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=3[C:13]2=[O:14])=[C:4]([F:20])[CH:3]=1
Reactant: CC(C)I
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 35.6 %

Procedure:
To a solution of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (2.95 g) in dimethylformamide (20 ml), there was added anhydrous potassium carbonate (0.8 g) while stirring at room temperature. After stirring for 10 minutes at about 40° C., isopropyl iodide (1.7 g) was added thereto, and the resultant mixture was stirred for 3 hours at 70°-80° C. After being allowed to cool to room temperature, the mixture was poured into water and extracted with toluene. The toluene layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain 1.2 g of N-(4-chloro-2-fluoro-5-isopropoxyphenyl)3,4,5,6-tetrahydrophthalimide (Compound No. 1). M.P., 81°-82° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]([O:7][C:8]([N:10]1[C:19]2[C:14](=[N:15][C:16](Br)=[CH:17][CH:18]=2)[C@H:13]([N:21]([C:37](=[O:39])[CH3:38])[CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:12][C@@H:11]1[CH2:40][CH3:41])=[O:9])([CH3:6])[CH3:5]>O.CS(C)=O>[CH:4]([O:7][C:8]([N:10]1[C:19]2[C:14](=[N:15][C:16]([N:2]([CH3:3])[CH3:1])=[CH:17][CH:18]=2)[C@H:13]([N:21]([C:37](=[O:39])[CH3:38])[CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:12][C@@H:11]1[CH2:40][CH3:41])=[O:9])([CH3:6])[CH3:5]
Reactant: CNC
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2nc(Br)ccc2N1C(=O)OC(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2nc(N(C)C)ccc2N1C(=O)OC(C)C
Temperature: 100 °C
Yield: 57 %

Procedure:
Add N,N-dimethylamine 40% in water (0.5 mL) to a solution of (+/-)-cis-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-bromo-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (60 mg, 0.098 mmol) in dimethylsulfoxide (0.2 mL) and heat the mixture at 100° C. in a sealed tube for 15 h. Cool the reaction mixture to room temperature, add water and extract with ethyl acetate. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Chromatograph the residue overa silica gel cartridge, eluting with hexanes/ethyl acetate to provide the title compound (32 mg, 57%). MS (ES+): 575 (M+H).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:8][CH2:9]C1(O)CCCCC1.COC1CCC(C(O)=O)CC1>>[Br:8][CH2:9][CH:4]1[CH2:5][CH2:6][CH:1]([OH:7])[CH2:2][CH2:3]1
Reactant: OC1CCCCC1
Reactant: OC1(CBr)CCCCC1
Agent: COC1CCC(C(=O)O)CC1
Product: OC1CCC(CBr)CC1

Procedure:
Modified polyvinylbutryal containing a pendant group with cyclohexanol was prepared by the reaction of PVB with tetrahydropyranyl (THP) protected bromomethylcyclohexanol, followed by acid hydrolysis of the THP protection group. The THP-protected cyclohexanol-containing moiety was prepared by the following reaction sequence: 4-Methoxycyclohexanoic acid was reduced with borane-tetrahydrofuran complex to obtain 4-bromomethyl-cyclohexanol. This compound was treated with phosphorus tribromide to obtain the corresponding bromo compound. This bromo compound was reacted with trimethylsilyliodide to cleave the methoxy group to obtain 4-bromomethyl-cyclohexanol, which in turn was treated with dihyhdropyran to obtain the tetrahydropyranyl-protected bromomethylcyclohexanol. This preparation is represented by the following reaction scheme and further described in paragraphs a-d below. ##STR3## a) Preparation of 4-bromomethylcyclohexanol (C-3)
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:9]([CH3:26])=[N:10][N:11]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][C:17]=4[CH3:24])=[C:14]([CH3:25])[O:13][C:12]=23)[N:3]=1.B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:9]([CH3:26])=[N:10][N:11]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=4[CH3:24])=[C:14]([CH3:25])[O:13][C:12]=23)[N:3]=1
Reactant: COc1ccc(-c2c(C)oc3c(-n4nc(C)nc4C)c(C)nn23)c(C)c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc(O)cc4C)c(C)oc23)n1
Reaction time: 0.5 h

Procedure:
7-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-3-(4-methoxy-2-methyl-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole (Ex. 6.12) (100 mg, 0.285 mmol) is dissolved in dry DCM (5 ml). The contents are flushed with N2 and to this solution is added boron tribromide (1.423 ml, 1.423 mmol) dropwise at RT. After approximately 30 mins, the reaction is quenched by careful addition of H2O. The mixture is transferred to a separating funnel and extracted with DCM (50 ml). The organic portion is separated and washed with 1M HCl, 1M NaOH, brine, dried (MgSO4) and evaporated in vacuo to give a brown solid. Trituration with EtOAc affords the title compound as an off white solid. MS m/z 338.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, 1H), 6.8 (s, 1H), 6.75 (d, 1H), 2.35 (s, 3H), 2.30 (s, 6H), 2.2 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[C:14]([O:21]C(=O)C)[CH:13]=1.Cl>CN(C)C1C=CC=CC=1.CC(C)=O.[OH-].[Na+]>[Cl:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([Cl:10])[C:5]=1[OH:9])[NH:1][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([CH3:11])=[CH:13][C:14]=1[OH:21]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(=O)Oc1cc(C)ccc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)Nc2cc(Cl)c(O)c(Cl)c2)c(O)c1
Yield: 72.5 %

Procedure:
4-Amino-2,6-dichlorophenol (16 g.) was put into solution in N,N-dimethylaniline (15 ml.) and acetone (200 ml.), to which the acetone solution of 4-methyl-2-acetoxybenzoyl chloride was added dropwise. After reaction for several hours, by condensing and then acidifying the solution with 4 N hydrochloric acid a precipitate was obtained, which was redissolved in 2 N sodium hydroxide solution. The solution was made acidic with dilute hydrochloric acid, thereby precipitating the product which was recrystallized from aqueous acetone to give white crystals (20.3 g.) of 3',5'-dichloro-2,4'-dihydroxy-4-methylbenzanilide. Yield: 72.5%. The melting point was 246°-247° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[S:10][C:3]=12.[CH3:14][NH:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([NH2:27])=[CH:24][CH:25]=2)[CH:20]=[C:19]1[CH3:28])=[O:17]>CS(C)=O>[CH3:28][C:19]1[N:18]([C:16](=[O:17])[NH:15][CH3:14])[C:26]2[C:21]([CH:20]=1)=[CH:22][C:23]([NH:27][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[S:10][C:3]=13)=[CH:24][CH:25]=2
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Reactant: CNC(=O)n1c(C)cc2cc(N)ccc21
Solvent: CS(C)=O
Product: CNC(=O)n1c(C)cc2cc(Nc3ccnc4cc(C(=O)O)sc34)ccc21
Temperature: 75 °C
Reaction time: 14 h
Yield: 91.9 %

Procedure:
To 0.68 g (1.23 mmol) of 7-Chloro-thieno[3,2-b]pyridine-2-carboxylic acid, prepared as described in Groton patent, was added 0.25 g (1.23 mmol) of 5-Amino-2-methyl-indole-1-carboxylic acid methylamide, prepared as described in Example 1(a) steps (i) to (iii), dissolved in 3 mL of DMSO that was degassed with Ar and warmed to 75° C. The solution was stirred for 14 h, cooled to 25° C. and filtered. The precipitate was rinsed with EtOAc (2×5 mL) and put under high vacuum for 12 h to give 0.43 g (98%) of 7-(2-Methyl-1-methylcarbamoyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridine-2-carboxylic acid as yellow solid. HPLC: Rt 3.38 min. (97.2% area). 1H NMR (CDCl3, 300 MHz) δ 9.18 (1H, bs), 8.37 (1H, d, J=5.6 Hz), 8.30 (1H, q, J=3.4 Hz), 7.94 (1H, s), 7.70 (1H, d, J=8.7 Hz), 7.46 (1H, s), 7.17 (1H, dd, J=8.8, 1.9 Hz), 6.79 (1H, d, J=5.6 Hz), 6.45 (1H, s), 2.96 (3H, s), 2.94 (3H, s). LCMS (APCI) (M+H+) m/z: 381.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([NH:31][S@@:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].I[CH:45]([CH3:47])[CH3:46]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C:9]([NH:31][S@@:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)(C)[S@@](=O)NC(Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(O)c(F)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Oc1ccc(C(Cc2ccccc2)(N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1F
Yield: 125.2 %

Procedure:
At rt to a solution of 4:1 diastereomeric mixture (R)—N-(1-(3-fluoro-4-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (578 mg, 1.06 mmol) in DMF (10 mL) was added K2CO3 (800 mg, 5.80 mmol) and the slurry was stirred vigorously. 2-Iodopropane (220 mg, 1.27 mmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with ether (50 mL), washed successively with 10% LiCl (2×20 mL) and water (20 mL). The organic portion was dried over Na2SO4, filtered and concentrated to yield (R)—N-(1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide as a pale orange foam (780 mg, 100% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[O:12]=[C:9]1[CH2:8][O:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]=2[NH:10]1
Reactant: O=C1COc2cccc(O)c2N1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1NC(=O)CO2
Temperature: 27 °C
Reaction time: 16 h

Procedure:
A solution of 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.604 mmol) and K2CO3 (167 mg, 1.21 mmol) in anhydrous DMF (5 mL) was stirred at 27° C. for 5 minutes, then ethyl 2-bromoacetate (121 mg, 0.727 mmol) was added. The reaction mixture was stirred at 27° C. for 16 h and concentrated. MS (ESI+) e/z: 238.0 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:18][O:17]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C(O)C>[C:20]([NH:24][CH2:18][C@H:16]([C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:6](=[O:19])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:9])=[CH:11][CH:12]=1)[OH:17])([CH3:23])([CH3:22])[CH3:21]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc([C@H]2CO2)cc1
Reactant: CC(C)(C)N
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc([C@H](O)CNC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
4.4 g of the compound [5-4] was dissolved in 40 mL of ethanol, 20 mL of tert-butylamine was added thereto, and the mixture was stirred for 3 days at 50° C. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-0/100), to obtain 3.1 g of tert-butyl ((1S)-1-{4-[(1S)-2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)carbamate [5-5] (hereinafter, referred to as the compound [5-5]) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:20][CH2:21][CH2:22][O:23][C:24](Cl)=[O:25].O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:24](=[O:25])[O:23][CH2:22][CH2:21][Cl:20])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCCCl
Reactant: NCCCN1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCCN1CCN(Cc2ccccc2)CC1)OCCCl
Reaction time: 24 h

Procedure:
To a stirred solution of 3-(4-benzyl-1-piperazinyl)propylamine (2.01 g/8.61 mmol) in tetrahydrofuran (15 ml) were added 2 N NaOH (6.5 ml/13.0 mmol) and 2-chloroethylchloroformate (1.38 ml/12.9 mmol), and the mixture was stirred for 1 d. Water (50 ml) was added to the mixture and the whole was extracted with ethyl acetate (50 ml). The extract was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/dichloromethane) to give a colorless oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[C:24]([F:39])=[C:25]([C:30]3[C:31]([C:37]#[N:38])=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[C:26]([F:29])=[CH:27][CH:28]=2)O1>>[OH:14][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:27]3[C:26]([F:29])=[C:25]([C:30]4[C:31]([C:37]#[N:38])=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[C:24]([F:39])=[CH:23][CH:28]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2F)OC1(C)C
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3F)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,2′,6′-trifluorobiphenyl-2-carbonitrile as described in Example 65 to give 3′-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]-4,2′,6′-trifluorobiphenyl-2-carbonitrile as an off-white solid: δH (400 MHz, d6-DMSO) 1.51 (6H, s), 7.42 (1H, d, J 7), 7.54-7.58 (1H, m), 7.80-7.85 (1H, m), 7.89-7.96 (3H, m), 8.14 (1H, dd, J 9 and 2), 8.78 (1H, dd, J 7 and 3).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([F:23])[C:21]=1[F:22])[NH2:18]>C(#N)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[NH:18][C:17]1[CH:16]=[C:15]([F:14])[C:21]([F:22])=[C:20]([F:23])[CH:19]=1
Reactant: Nc1cc(F)c(F)c(F)c1
Reactant: COC(=O)C(Br)c1cccc(F)c1
Solvent: CC#N
Product: COC(=O)C(Nc1cc(F)c(F)c(F)c1)c1cccc(F)c1
Temperature: 120 °C
Yield: 53.3 %

Procedure:
Methyl 2-bromo-2-(3-fluorophenyl)acetate (300 mg, 1.21 mmol) and 3,4,5-trifluoroaniline (268 mg, 1.82 mmol) were dissolved in acetonitrile (4 ml) and stirred under microwave heating into a sealed vial at 120° C. for 1 hours. Some crystals of KI were added, and the resulting mixture was stirred under the same conditions for 1 hour (UPLC-MS: conversion complete). Solvent was evaporated, and the crude residue was purified by flash chromatography (Petroleum ether/EtOAc=9/1) to obtain (3-fluoro-phenyl)-(3,4,5-trifluoro-phenylamino)-acetic acid methyl ester (202 mg, 53% yield).