Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].COCCOC.Br[C:14]1[CH:18]=[CH:17][S:16][CH:15]=1.CC1(C)C(C)(C)OB([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)O1>O.C(OCC)(=O)C>[S:16]1[CH:17]=[CH:18][C:14]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)=[CH:15]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Brc1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(-c2ccsc2)cc1
Temperature: 25 °C

Procedure:
An aqueous sodium carbonate solution and tetrakis triphenylphosphine palladium were added to a DME solution of 3-bromothiophene and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, and the mixture was refluxed under heating for 6 hours with argon atmosphere. After cooling to room temperature, the reaction mixture was added with ethyl acetate and water to separate an organic layer, which was then washed and dried. The solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography, to obtain 4-(3-thienyl)aniline (pale yellow solid). Electron Impact-MS (M)+: 175.
Reaction SMILES: Cl.[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13].CCN(C(C)C)C(C)C.CO>C(Cl)Cl>[F:2][C:3]1([F:10])[CH2:8][CH2:7][CH:6]([NH:9][C:12](=[O:13])[O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)[CH2:5][CH2:4]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1CCC(F)(F)CC1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CCC(F)(F)CC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,4-difluorocyclohexanamine hydrochloride (Matrix scientific, 250 mg, 1.45 mmol) in DCM (5 mL) was added 4-nitrophenyl chloroformate (367 mg, 1.82 mmol) and DIEA (507 μl, 0.29 mmol). The resulting mixture was then stirred at RT for 16 h. Then, MeOH (2 mL) was added and the solvents were removed. The residue was purified by silica gel flash column chromatography (0%-100% EtOAc/hexane) to give the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[C:4]([OH:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C[C:25](=[O:28])[CH2:26][CH3:27]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[C:4]([O:17][CH2:27][CH:26]2[O:28][CH2:25]2)[CH:3]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(Cl)cc1O
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCC(=O)c1ccc(Cl)cc1OCC1CO1
Yield: 86 %

Procedure:
A well stirred mixture of ethyl 3-(4-chloro-2-hydroxybenzoyl)propionate (9.6 g, 0.037 mole), potassium carbonate (5.96 g, 0.043 mole) epibromohydrin (14.4 ml, 0.173 mole) and dry butan-2-one (250 ml) was heated under reflux for 28 hours. Evaporation of the filtered solution under reduced pressure and purification of the residue by column chromatography gave ethyl 3-[4-chloro-2-(2,3-epoxypropoxy)benzoyl]-propionate as an oil (10.0 g, 86%). (Found: M+, 312/314. C15H17ClO5. requires M, 312/314).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:25]1([NH:28][C:29]([NH:31][NH2:32])=[S:30])[CH2:27][CH2:26]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.CCO>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:32][NH:31][C:29](=[S:30])[NH:28][CH:25]3[CH2:27][CH2:26]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:8]=1
Reactant: NNC(=S)NC1CC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC(=S)NC1CC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 9.1 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.5 g, 1.0 eq.) was dissolved in EtOAc:EtOH (15 mL, 2:1) and cooled to −60° C. where N-cyclopropylhydrazinecarbothioamide (0.22 g, 1.2 eq.) was introduced dropwise. T3P (50% in EtOAc) (1.69 mL, 2 eq.) was added dropwise followed by DIPEA (1 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-N-cyclopropylhydrazinecarbothioamide (0.06 g, yield: 9%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=2)=[CH:23][CH:22]=1)[CH3:19]>C1(C)C=CC=CC=1>[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:3]3[C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=[C:2]3[CH3:1])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1)[CH3:19]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CCOc1ccc(Oc2ccc(CCl)cc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOc1ccc(Oc2ccc(Cn3c(C)nc4ccccc43)cc2)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A mixture of toluene (20 ml), 2-methylbenzimidazole (0.55 g, 4.2 mmole), triethylamine (0.42 g, 4.2 mmole) and 4-(4-ethoxyphenoxy)benzyl chloride (1.00 g, 3.8 mmole) was heated under reflux for 5 hours and then cooled to room temperature. The resultant mixture was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 1-[4-(4-ethoxyphenoxy)benzyl]-2-methylbenzimidazole (1.20 g) as colorless liquid. nD26.0 1.5984.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:36]1([CH2:42][CH2:43][S:44][CH:45]([C:49](O)=[O:50])[C:46](O)=[O:47])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[OH:50][C:49]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[C:12]([CH3:20])[CH:13]=2)[O:19][C:46](=[O:47])[C:45]=1[S:44][CH2:43][CH2:42][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1ccccc1COc1ccc(C(C)=O)cc1C
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1C

Procedure:
The title compound was prepared by Method A using 4'-[(2-methoxyphenyl)methoxy]-3'-methylacetophenone (1.36 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. dec. 170° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3 H), 2.77 (t, 2 H), 2.97 (t, 2 H), 3.84 (s, 3 H), 5.17 (s, 2 H), 6.67 (s, 1 H), 6.98 (t, 1 H), 7.70 (d, 1 H), 7.27 (m, 6 H), 7.41 (t, 1 H), 7.43 (d, 1 H), 7.65 (m, 2 H), 11.81 (bs, 1 H).
Reaction SMILES: C([O:4][N:5]1[C:10]([NH2:11])=[CH:9][C:8](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:7][C:6]1=[NH:23])(=O)C.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[NH2:11][C:10]1[N:5]([OH:4])[C:6](=[NH:23])[N:7]=[C:8]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:9]=1
Reactant: CC(=O)On1c(N)cc(OS(=O)(=O)c2ccc(C)cc2)nc1=N
Reactant: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: N=c1nc(N2CCCCC2)cc(N)n1O
Reaction time: 1 h
Yield: 75 %

Procedure:
0.3 g (0.88 mmole) of 1-acetoxy-6-amino-1,2-dihydro-2-imino-4-(4-toluenesulfonyloxy)pyrimidine is added to a solution containing 10 ml of chloroform and 2 ml of piperidine while stirring. The mixture is refluxed under stirring for 30 minutes, then evaporated under reduced pressure. To the residue, 5 ml of ethanol and 1 ml of 1N aqueous sodium hydroxide solution are added. The mixture is set aside at room temperature for one hour, then evaporated under reduced pressure. The residue is triturated with 10 ml of water, the crystals are filtered, washed with water and dried to give 0.14 g (75% yield) of the aimed compound which shows no melting point depression when mixed with the product of Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[ClH:11]>[Pt]=O>[ClH:11].[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1
Reactant: OCCCc1ccncc1
Agent: O=[Pt]
Agent: Cl
Product: OCCCC1CCNCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.00 g (7.29 mmol) of 4-pyridinepropanol was dissolved in 3N aqueous hydrochloric acid solution and 206 mg of platinum oxide was added thereto, followed by stirring of the mixture at room temperature under a hydrogen atmosphere at an ordinary pressure for 12 hours. The reaction mixture was filtered with Celite and the filtrate was distilled off under reduced pressure. The thus obtained residue was reprecipitated from methanol-ether to obtain 1.31 g (yield: quantitative) of the title compound as a white solid.
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]1[CH2:29][CH:28]([OH:30])[CH2:27][CH:26]1[CH:31]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[O:32][CH:33]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([CH:33]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[O:32][CH:31]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:26]2[CH2:27][CH:28]([OH:30])[CH2:29][N:25]2[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:35][CH:36]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1

Procedure:
Using the above procedure Myristic acid (2.30 g, 10 mmol) was coupled with the amine 100 (6.10 g, 11.45 mmol) using HBTU (4.54 g, 1.2 eq.) and DIEA (5 mL, 3.00 eq). After work-up and column purification the pure amide 102c was isolated as a pale yellow solid (Yield, 6.10 g, 80%). 1H NMR (DMSO-d6, 400 MHz) δ=7.72-7.65 (m, 1H), 7.35-7.26 (m, 4H), 7.27-7.12 (m, 5H), 6.90-6.80 (m, 4H), 4.99 (d, J=3.91 Hz, 1H), 4.89 (d, J=3.91 Hz, 1H), 4.41-4.10 (m, 2H), 3.71 (s, 6H), 3.57-3.42 (m, 1H), 3.37-3.11 (m, 2H), 3.05-2.91 (m, 3H), 2.25-1.80 (m, 6H), 1.52-1.08 (m, 28H), 0.83 (t, J=6.34 Hz, 3H). 13C NMR (DMSO-d6, 400 MHz) δ=171.84, 170.93, 170.82, 158.11, 157.98, 145.09, 144.75, 135.87, 135.72, 135.47, 135.42, 129.60, 129.55, 127.84, 127.75, 127.72, 126.56, 113.17, 113.08, 85.78, 85.12, 68.58, 67.45, 65.19, 63.33, 55.61, 55.06, 54.99, 53.44, 39.08, 38.87, 38.22, 38.02, 36.31, 35.44, 34.18, 32.54, 31.32, 29.09, 29.04, 28.99, 28.80, 28.74, 28.64, 26.20, 25.34, 24.55, 24.15, 22.11, 13.93.
Reaction SMILES: C(O)(=O)C.C=O.[CH2:7]([C:9]1[C:17]([O:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([N:25]3[C:33](=O)C4C(=CC=CC=4)[C:26]3=O)[CH2:21][CH2:20]2)=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][NH:13]2)[CH3:8].C([BH3-])#N.[Na+].[OH-].[Na+]>>[CH2:7]([C:9]1[C:17]([O:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([N:25]([CH3:33])[CH3:26])[CH2:21][CH2:20]2)=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][NH:13]2)[CH3:8]
Reactant: CCc1c(O[C@H]2CC[C@H](N3C(=O)c4ccccc4C3=O)CC2)ccc2[nH]ncc12
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1c(O[C@H]2CC[C@H](N(C)C)CC2)ccc2[nH]ncc12
Reaction time: 8 h

Procedure:
Acetic acid (0.14 mL, 2.5 mmol) and an aqueous formaldehyde solution (209.3 mg, 2.5 mmol) were added to a methanolic solution (3 mL) of the trans-4-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine (130 mg, 0.5 mmol) obtained in Example 744, and then sodium cyanoborohydride (157.7 mg, 2.5 mmol) was added thereto and stirred overnight. A 1N-aqueous sodium hydroxide solution was added to the reaction solution, followed by extraction with chloroform (three times), and the extract solution was dried over anhydrous magnesium sulfate. The residue was purified by a silica gel chromatography (methanol:chloroform=0/100 to 10/100) to obtain trans-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylamine (82.3 mg, 57%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[CH3:30])[CH2:18]1)=[O:16])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[Cl:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([N:4]([CH2:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[CH3:30])[CH2:18]1)=[O:16])[CH2:3][CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CN(CCN)C(=O)c2cccc(Cl)c2)CC1=O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1N1CN(C(=O)CN(CCNS(C)(=O)=O)C(=O)c2cccc(Cl)c2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(2-Amino-ethyl)-3-chloro-N-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-benzamide (80 mg, 0.16 mmol, 1 eq), methanesulfonyl chloride (0.015 ml, 0.19 mmol, 1.2 eq), TEA (0.07 ml) in THF (1 ml) was stirred at room temperature overnight. It was purified with HPLC to give the desired product. LCMS observed for (M+H)+: 527.2
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)cc1F
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(Br)cc1F
Yield: 15369.9 %

Procedure:
Combine 4-bromo-2-fluoro-benzoic acid (5.0 g, 22.83 mmol), thionyl chloride (10 mL, 0.137 mmol) in toluene (10 mL) and reflux for 2 h. Evaporate the reaction mixture to obtain 4-bromo-2-fluoro-benzoyl chloride (5.0 g, 93%) and use for the next step without further purification. Dissolve tert-butylamine (0.8 mL, 5.12 mmol) and triethylamine (0.8 mL, 6.32 mmol) in anhydrous DCM (20 mL), cool to 0° C. and add a solution of 4-bromo-2-fluoro-benzoyl chloride (1.0 g, 4.22 mmol) in anhydrous DCM (10 mL). Stir the reaction mixture at 0° C. for 10 min, warm to ambient temperature and continue to stir for 30 min. Wash the reaction mixture with brine (2×10 mL), dry the organic extracts over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with DCM to obtain the desired intermediate as a white solid (1.0 g, 87%). MS (ES+) m/z: 275 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH:18]2[CH2:20][CH2:19]2)[N:3]=1.[K].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH:18]3[CH2:20][CH2:19]3)[N:3]=2)(=[O:33])=[O:34])=[CH:28][CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(C2CC2)nc1Cl
Agent: [K]
Product: COc1ccccc1Oc1c(Cl)nc(C2CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
According to the procedure described in Example 1g) 3.3 g 4,6-dichloro-2-cyclopropyl-5-(o-methoxyphenoxy)-pyrimidine (prepared according to procedures described in Example 1) was reacted with 4-tert.-butylphenylsulfonamide potassium salt to give 4.22 g 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide. LC-MS: tR=6.24 min, [M+1]+=488.23.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[NH:8][C:9](=[O:17])[N:10]([CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH:11]=1)=[O:5])[CH3:2].[CH3:25][Si](C)(C)N[Si](C)(C)C.[K].CI.[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:8]([CH3:25])[C:9](=[O:17])[N:10]([CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCCOCN1C=C(C(=O)OCC)C(c2ccc(F)cc2)NC1=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [K]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCOCN1C=C(C(=O)OCC)C(c2ccc(F)cc2)N(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
To a solution of 4-(4-Fluoro-phenyl)-2-oxo-1-propoxymethyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (152 mg, 0.39 mmol) in THF (3 mL) was added potassium hexamethyldisilazane (0.92 mL of 1M toluene solution, 0.46 mmol) at 0° C. under Ar. The mixture was stirred for 1 h at 0° C. Methyl iodide (0.23 mL of 2M solution in tert-butyl methyl ether) was added at 0° C., and the mixture was stirred at 0° C. overnight. Saturated aqueous NH4Cl was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried under Na2SO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash column (hexane/ethyl acetate gradient) gave 4-(4-fluoro-phenyl)-3-methyl-2-oxo-1-propoxymethyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (143 mg, 91%).
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([C@H:7]1[CH2:11][C@@H:10]([F:12])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O>C1COCC1>[C:16]([O:15][C:13]([N:8]1[CH2:9][C@H:10]([F:12])[CH2:11][C@@H:7]1[CH2:5][OH:4])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)[C@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@@H]1CO
Temperature: 25 °C
Yield: 80.5 %

Procedure:
Add lithium borohydride (1.03 g, 47.4 mmol) to an ice cold solution of 4-(R)-fluoropyrrolidine-N1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7.8 g, 31.5 mmol) in THF (100 mL). Let warm to room temperature over 18 h. Cool in ice bath. Slowly add acetic acid (5 mL) and water and extract with ethyl acetate. Wash extract with water, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a thick oil (5.56 g, 80%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]#[C:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[N:27][CH:26]=[CH:25]3)[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[C:39](B(O)O)=[C:38]([CH3:43])[O:37][N:36]=1.[F-].[Cs+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C(Cl)Cl.O1CCOCC1>[C:1]([O:5][C:6](=[O:33])[N:7]([CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:39]2[C:35]([CH3:34])=[N:36][O:37][C:38]=2[CH3:43])=[C:15]([C:20]#[C:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[N:27][CH:26]=[CH:25]3)[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C(=O)Nc1ccc(Br)c(C#Cc2ccc3cnccc3c2)n1)N(C)C(=O)OC(C)(C)C
Reactant: Cc1noc(C)c1B(O)O
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2cnccc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-bromo-6-(2-isoquinolin-6-ylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate C2b (300 mg, 0.59 mmol), (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid (166 mg, 1.18 mmol), CsF (358 mg, 2.36 mmol) tris-(dibenzylideneacetone)dipalladium(0) (41 mg, 0.06 mmol), tri-tert-butylphosphonium tetrafluoroborate (34 mg, 0.12 mmol) and dioxane (4.5 ml) is stirred under argon atmosphere at 50° C. for 2 h. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 191 mg (62%). HPLC-MS: M+H=526; tR=1.89 min (*Method—2).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([F:19])=[C:14]([CH:18]=1)[C:15](Cl)=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([F:19])=[C:14]([CH:18]=1)[C:15]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1)=[O:16]
Reactant: CN1CCC(N)CC1
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(NC(=O)c2cc(Cl)ccc2F)CC1

Procedure:
A mixture of 23.9 g 4-amino-1-methyl-piperidine, 48.5 g 5-chloro-2-fluoro-benzoyl chloride, 44 ml triethylamine and 550 ml benzene is refluxed for 2 hours. Thereafter the solvent is evaporated off in vacuo and the residue is added dropwise under stirring to water. The solution is made alkaline and extracted with toluene. The toluene phase is dried and evaporated. The residue is recrystallised from methylene chloride/ether/petroleum ether to give the heading compound, m.p. 143°-145°.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>CN(C=O)C>[CH3:15][O:16][C:17]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([O:21][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20]
Reactant: COc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C(=O)OCc2ccccc2)cccc1[N+](=O)[O-]
Reaction time: 1.17 h

Procedure:
At room temperature, benzyl bromide (8.85 mL) and potassium carbonate (10.3 g) were added to a DMF (150 mL) solution of 2-methoxy-3-nitrobenzoic acid (9.80 g), followed by stirring for 70 minutes. The insoluble matter was separated by filtration, followed by evaporation under reduced pressure. This was subjected to liquid-liquid separation with ethyl acetate, aqueous sodium hydrogencarbonate solution, and hexane added thereto. The organic layer was washed with water and saturated brine in that order, dried, and then evaporated under reduced pressure to obtain benzyl 2-methoxy-3-nitrobenzoate (14.3 g).
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[NH2:8][CH2:9][CH2:10][NH2:11]>C(O)C>[O:6]=[S:1]1(=[O:7])[CH2:5][CH2:4][CH:3]([NH:8][CH2:9][CH2:10][NH:11][CH:3]2[CH2:4][CH2:5][S:1](=[O:7])(=[O:6])[CH2:2]2)[CH2:2]1
Reactant: O=S1(=O)C=CCC1
Reactant: NCCN
Solvent: CCO
Product: O=S1(=O)CCC(NCCNC2CCS(=O)(=O)C2)C1

Procedure:
To a 500 ml. round bottom flask equipped with condenser, thermometer and a stirrer were introduced 118 g. (1.0 mole) of 4,5-dihydrothiophene 1,1-dioxide, 200 ml. of 70% by weight aqueous ethanol and 30 g. (0.5 mole) of 1,2-diaminoethane (ethylenediamine). The reaction mixture was heated at reflux (80°-85°C) for 4 hours. The solvent was then removed under a reduced pressure. The product, N,N'-bis(1,1-dioxotetrahydro-3-thienyl)-1,2-diaminoethane, obtained was a viscous liquid that became a solid, m.p. 60°-85°C. IR spectrum showed absorptions at 3300 cm-1 (NH), at 1300 cm-1 and 1140 cm-1 (SO2).