Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[OH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11](=[O:19])[C:10]2=[C:20]([CH3:23])[CH:21]=[CH:22][N:9]2[N:8]=1)[NH3+:6].[Br:24][C:25]1[C:33]2[C:32](Cl)=[N:31][CH:30]=[N:29][C:28]=2[N:27]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:26]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[Br:24][C:25]1[C:33]2[C:32]([NH:6][C@H:5]([C:7]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11](=[O:19])[C:10]4=[C:20]([CH3:23])[CH:21]=[CH:22][N:9]4[N:8]=3)[CH2:4][CH2:3][OH:2])=[N:31][CH:30]=[N:29][C:28]=2[N:27]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:26]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Cl)ncnc21
Reactant: Cc1ccn2nc([C@@H]([NH3+])CCO)n(-c3ccccc3)c(=O)c12
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: Cc1ccn2nc([C@H](CCO)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 96 h
Yield: 58.6 %

Procedure:
(S)-3-Hydroxy-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propan-1-aminium chloride (228 mg, 0.68 mmol) was treated with 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (495 mg, 1.36 mmol), cesium fluoride (41 mg, 0.27 mmol) and N,N-diisopropylethylamine (1.60 ml, 9.19 mmol) in tert-butanol (5.0 ml) according to Preparation 13 but stirring the reaction mixture at 100° C. during 96 h. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 249 mg (57% yield) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13](=O)[CH3:14])[CH:10]=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][O:27][CH3:28].Cl.N1C=CC=CC=1>CCO>[CH3:28][O:27][N:26]=[C:13]([C:11]1[CH:10]=[CH:9][C:8]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1)[CH3:14]
Reactant: CON
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(C)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure P, 1-[6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-ethanone (Compound 77, 15 mg, 0.04 mmol), NH2OMe—HCl (15 mg, 0.18 mmol) and pyridine (14 mg, 0.18 mmol) in EtOH (2 ml) were reacted to give title compound as a white solid. (12 mg, 75%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][O:14][C:15]1[C:16]([N+]([O-])=O)=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.O>CN(C=O)C>[CH3:13][O:14][C:15]1[C:16]2[S:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:18][C:17]=2[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cccc(OC)c2s1
Temperature: 70 °C

Procedure:
550 mg (3.97 mmol) of potassium carbonate and 350 mg (3.31 mmol) of methyl mercaptoacetate are added to a solution of 600 mg (3.31 mmol) of 3-methoxy-2-nitrobenzaldehyde in 8 ml of DMF. The reaction mixture is heated at 70° C. for 4 h. After cooling, water is added. The resulting precipitate is filtered off, washed with water and dried under reduced pressure. This gives 387 mg (45.7% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH2:45]([O:52][C:53]1[CH:60]=[CH:59][C:56]([CH:57]=[O:58])=[CH:55][CH:54]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[C@@H:15]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:19][CH:18]=1)[C@@H:57]([C:56]1[CH:59]=[CH:60][C:53]([O:52][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:54][CH:55]=1)[OH:58])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)c1ccc(OCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(O[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](O)c2ccc(OCc3ccccc3)cc2)cc1

Procedure:
The target compound (30.0 g) was obtained as a colorless oil by carrying out the reaction and the post-treatment according to Reference example 20(b) using (S)-4-benzyl-3-[(4-t-butylphenoxy)acetyl]oxazolidin-2-one (28.2 g) obtained from Reference example 21(a), a solution of dibutylboron triflate in dichloromethane (1M, 92.1 ml), triethylamine (13.9 ml) and 4-benzyloxybenzaldehyde (17.9 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][S:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:36]=[N:37][C:32]([S:31][CH3:30])=[CH:33][CH:34]=3)=[CH:3][CH:4]=2)[N:9]=[C:10]([C:20]([C:22]([F:23])([F:25])[F:24])([C:26]([F:29])([F:27])[F:28])[OH:21])[CH2:11]1
Reactant: OC(C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Reactant: CSc1ccc(B(O)O)cn1
Product: CSc1ccc(-c2ccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)cc2)cn1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Example 421, except for using 1-(4-bromo-phenyl)-5-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole prepared in Step 5 of Preparation 24; and using 6-methylthiopyridin-3-ylboronic acid instead of 3-methylthiophenylboronic acid.
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.C1C=CC=CC=1.[Cl:49][CH2:50][CH2:51][CH2:52]O>>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[Cl:49][CH2:50][CH2:51][CH2:52][O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Reactant: OCCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: c1ccccc1
Solvent: O
Product: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)OCCCCl)cccc12
Temperature: 100 °C
Yield: 88 %

Procedure:
A mixture of 1.0 gram of N2 -dansyl-L-arginine and 1.4 gram of p-toluenesulfonic acid monohydrate in 10 ml of 3-chloro-1-propanol was heated for 30 minutes at 100° C. To the thus obtained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 5 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 100 ml of ethyl ether was added to the residue to give a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine 3-chloropropyl ester di(p-toluenesulfonate) in 88% yield; mp. 140°-145° C.
Reaction SMILES: [CH:1]1([CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11][N:12]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.O.NN.[OH-].[Na+].O>C(O)C>[CH:1]1([CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(C=CC2CC2)s1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCc1ccc(C=CC2CC2)s1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
2-(5-(2-Cyclopropylvinyl)thiophen-2-ylmethyl)isoindol-1,3-dione described in Preparation Example 150 (330 mg, 1.02 mmol) was dissolved in ethanol (50 mL), hydrazine monohydrate (500 mg, 10 mmol) was added thereto, and the solution was stirred under reflux for 2 hours. After cooling to room temperature, 2N sodium hydroxide solution (10 mL) and water (100 mL) were added to the reaction solution, which was then washed twice with hexane (50 mL). The organic layer was dried over anhydrous sodium sulfate, then, the solvent was evaporated in vacuo, and the title compound (180 mg, 1.01 mmol, 98.6%) was obtained as a colorless oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[CH:11][C:10]([C:13]([O:15]C)=O)=[CH:9][N:8]=1.[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:13]([C:10]3[CH:11]=[N:12][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:17])=[N:8][CH:9]=3)=[O:15])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1cnc(N2CCCS2(=O)=O)nc1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 17.4 %

Procedure:
Using methyl 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)pyrimidine-5-carboxylate (100 mg) described in Preparation Example 231 and 1-(3,5-dimethylpyridin-2-yl)piperazine (74 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (28 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH2:8].[S:9]1[CH2:15][C:13](=[O:14])[NH:12][C:10]1=S.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH:8][C:10]1[S:9][CH2:15][C:13](=[O:14])[N:12]=1
Reactant: O=C1CSC(=S)N1
Reactant: Cc1ccsc1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccsc1CNC1=NC(=O)CS1
Temperature: 0 °C
Reaction time: 72 h
Yield: 31.3 %

Procedure:
To a solution of 3-methyl-thiophen-2-ylmethylamine (700 mg, 5.5 mmol) and rhodanine (732 mg, 5.5 mmol) in acetonitrile (30 mL) was added diisopropylethylamine (DIEA) (1.91 mL, 11 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (1.52 g, 5.6 mmol) was added in one portion. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with acetonitrile (200 mL) and ethyl acetate (250 mL). The filtrates were removed under the vacuum and the crude residue was dissolved in dichloromethane (150 mL) and washed with water and brine solution. After drying over magnesium sulfate, the filtrate was removed under the vacuum and the residue was dissolved in dichloromethane (10 mL) and diluted with hexanes (10 mL). After overnight storage in the refrigerator, the solids were collected by filtration and washed with dichloromethane. After drying in air, 390 mg (31.5% yield) of 2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one was isolated as a light yellow amorphous solid: EI-HRMS m/e calcd for C9H10N2OS2 (M+) 226.0235, found 226.0232.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C@H:6](O)[CH3:7])=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].C1CCN2C(=NCCC2)CC1.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([N:11]=[N+:12]=[N-:13])[CH3:7])=[CH:4][CH:3]=1
Reactant: C[C@@H](O)c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](N=[N+]=[N-])c1ccc(F)cc1
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a cooled solution (−15° C.) of the product of Step 1 (23.5 g, 0.168 mol) in toluene (300 ml) was added diphenylphosporyl azide (55.4 g, 0.395 mol) followed by DBU (30.4 ml, 0.2 mol). After stirring overnight, the resulting biphasic solution was poured into 500 ml 1 N HCl. The aqueous layer was extracted with toluene and the combined organic layers were washed with water, 1 N HCl and dried over Na2SO4. After removal of solvent, 25 g of crude product was obtained and was carried on to next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:5][C:6]=1[CH:7]([OH:11])[CH2:8][CH:9]=[CH2:10].[OH2:22].[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)[S:5][C:6]=1[CH:7]([OH:11])[CH2:8][CH2:9][CH2:10][OH:22]
Reactant: O
Reactant: C=CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCCO
Reaction time: 1 h

Procedure:
To a solution of [rac]-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-but-3-en-1-ol [200 mg, 0.64 mmol; PCT Int. Appl. (2002), WO 02/062774 A1] in tetrahydrofuran (2 ml) was added a 1 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (1.28 ml, 1.28 mmol) at ambient temperature under an argon atmosphere. The yellow solution was stirred for 1 h, water (1 ml), 3 M aqueous NaOH solution (0.2 ml) and 35% aqueous H2O2 solution (0.2 ml) were added and stirring was continued for 1 h. Water and ethyl acetate were added, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed two times with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give 212 mg (0.64 mmol, quant.) of the title compound which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[N:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[N:7]=[N:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[N:4][CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Fc1cccc(F)c1-c1ncc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1cccc(F)c1-c1ncc(Oc2cccc(Cl)c2)nn1
Reaction time: 2 h

Procedure:
325 mg of 6-chloro-3-(2,6-difluorophenyl)-[1,2,4]triazine (see Example 1.7 b) are placed in 10 ml of acetonitrile; 230 mg of 3-chlorophenol and 190 mg of potassium carbonate are added and stirring is carried out at room temperature for 2 h. The reaction mixture is then poured into water and extracted with ethyl acetate; the ethyl acetate phase is concentrated and the crude product is purified by means of flash chromatography. In this way the title compound having a melting point of 132-137° C. is obtained.
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1.[BH4-].[Na+].C[OH:23]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]2[C:5]([CH:4]([OH:23])[CH3:3])=[CH:6][N:7]=[CH:8]2)=[CH:12][CH:13]=1)#[N:18]
Reactant: COC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cncn1Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the ester from Example 1, step C, (1.50 g, 5.88 mmol), in methanol (20 ml) at 0° C., was added sodium borohydride (1.0 g, 26.3 mmol) portionwise over 5 minutes. The reaction was stirred at 0° C. for 1 hr and then at room temperature for an additional 1 hr. The reaction was quenched by the addition of sat. NH4Cl solution and the methanol was evaporated in vacuo. The residue was partitioned between EtOAc and sat NaHCO3 solution and the organic extracts dried (MgSO4), and evaporated in vacuo. The residue was purified by chromatography (SiO2, 4 to 10% methanol in methylene chloride, gradient elution) to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11]Br)=[C:9]([Br:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=1)=[O:5])[CH3:2].[SH:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][S:20][C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)=[C:9]([Br:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1CBr
Reactant: Sc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1CSc1ncc[nH]1
Temperature: 85 °C

Procedure:
To a solution of ethyl-5-bromo-4-(bromomethyl)-1-phenyl-1H-pyrazole-3-carboxylate (2.1 g, 5.44 mmol, 1 eq) and 2-mercaptoimidazole (0.6 g, 5.98 mmol, 1.1 eq) in ACN (30 mL) is added dry K2CO3 (2.25 g, 16.32 mmol, 3 eq) and the reaction mixture is heated at 85° C. for 1 h. The reaction mixture is diluted with DCM and filtered. The filtrate is concentrated and the residue is partitioned between DCM/water. The organic layer is dried over Na2SO4 and concentrated to afford the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 12.29 (bs, 1H), 7.59-7.53 (m, 5H), 7.16 (d, J=1.4 Hz, 1H), 6.94 (d, J=1.4 Hz, 1H), 4.28-4.26 (m, 2H), 4.19 (s, 2H), 1.29 (t, J=7.7 Hz, 3H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)O1.Br[C:35]1[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:14]([N:12]1[CH:13]=[CH:9][C:10]([C:35]2[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=2)=[N:11]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ncccc1Br
Reactant: CC1(C)OB(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ncccc1-c1ccn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 95 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
4-(4,4,5,5-Tetramethyl-(1,3,2)dioxaborolan-2-yl)-1-trityl-1H-pyrazole (3.2 g, 7.33 mmol) described in Manufacturing Example 32-1-2, 3-bromo-pyridine-2-ylamine (1.14 g, 6.60 mmol), tetrakis (triphenylphosphine)palladium (0) (424 mg, 0.37 mmol), toluene (40 mL), 2 M aqueous sodium carbonate solution (10 mL) and ethanol (20 mL) were stirred for 1 hour at 95° C. The reaction solution was allowed to room temperature, and partitioned into water and ethyl acetate. The ethyl acetate layer was washed with water once, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=1:2) to obtain the title compound (2.3 g, 78.0%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH2:27][C@H:26]5[OH:34])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Temperature: 130 °C
Yield: 3.7 %

Procedure:
A stirred mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole from Example 29 (210 mg, 0.3 mmol), (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (92 mg, 0.6 mmol), and DIEA (267 μL, 1.5 mmol) in DMA (3 mL) was heated at 130° C. for 120 h in a sealed tube. The mixture was cooled to rt and subjected to purification by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-1-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (5.4 mg, 4%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.36-8.54 (m, 3H), 7.71 (s, 1H), 7.35 (m, 1H), 7.11-7.30 (m, 5H), 5.51 (s, 2H), 5.18 (t, J=7.0 Hz, 1H), 4.30 (m, 1H), 3.16 (dd, J=7.2, 15.8 Hz, 1H), 2.74 (dd, J=7.3, 15.4 Hz, 1H). LCMS (ESI) m/z 492 and 494 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C@@H:37](O)[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][C@@H:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30]([F:29])([F:40])[F:41])[CH3:38])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@H](O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O[C@H](C)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B31, 7.3 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-hydroxythiophene-2-carboxylate, 5.0 g of (1S)-1-[2-(trifluoromethyl)phenyl]ethanol, 9.2 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 8.1 g of di-tert-butyl azodicarboxylate in 180 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:36]1([CH2:42][C:43](Cl)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)(Cl)Cl>[C:36]1([CH2:42][C:43]([N:16]2[CH2:15][CH:14]([O:13][C:12]3[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:27])[F:28])=[CH:10][CH:11]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17]2)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C(O)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of 2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 1 (5.8 g. 0.019 mole) and triethylamine (2.3 g, 0.023 mole) in chloroform (75 ml) was slowly dropped phenylacetyl chloride (3.5 g. 0.023 mole) in chloroform (10 ml). After stirring at ambient temperature overnight the reaction mixture was concentrated to an oil. The oil was dissolved in ether, then washed with water, dilute HCl (10%), again with water and dried (saturated NaCl, anhydrous (MgSO4). The solution was filtered, concentrated to an oil which was extracted with boiling hexanes and then concentrated to an oil (6.8 g, 84%). A sample was distilled to yield an oil of 3-phenylacetyl-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, 240°-250° C./0.1 mm.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][CH2:14][CH2:15]Br>C(Cl)Cl.CO>[C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:15][CH2:14][O:13][CH3:12])[C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: Cc1nc(N)sc1C(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: COCCn1c(C)c(C(C)(C)C)sc1=N
Temperature: 85 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
A mixture of 5-tert-butyl-4-methylthiazole-2-ylamine (1.5 g, 8.8 mmol) and 2-bromoethyl methyl ether (0.91 mL, 9.7 mmol) was warmed to 85° C. and allowed to stir for 24 hours. The crude material was dissolved in ˜5 mL of a 1:1 mixture of CH2Cl2 and CH3OH and a small amount of silica gel was added. This mixture was concentrated to dryness and the residue was purified via flash column chromatography (SiO2, 9:1:0.1 CH2Cl2:CH3OH:NH4OH) to afford the title compound (1.0 g, 4.4 mmol, 50% yield). 1H NMR (300 MHz, CD3OD) δ ppm 1.41 (s, 9H) 2.38 (s, 3H) 3.35 (s, 3H) 3.66 (t, J=4.70 Hz, 2H) 4.16 (t, J=4.70 Hz, 2H); MS (DCI/NH3) m/z 229 (M+H)+.