Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:32]([F:35])([F:34])[F:33])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]4[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C:19]=4[NH:20][N:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O.C(Cl)[Cl:44]>>[ClH:44].[F:1][C:2]1[C:3]([C:32]([F:33])([F:34])[F:35])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]4[CH2:24][NH:23][CH2:22][C:19]=4[NH:20][N:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]nc(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)c2C1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(c1n[nH]c2c1CNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a mixture of tert-butyl 3-(4-(3,4-difluoro-2-(trifluoro-methyl)phenyl) piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (37, 0.132 g, 0.26 mmol) and CH2Cl2 (1 mL) was added TFA (1 mL). The mixture stirred at ambient temperature for 2 h and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and the solution was washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2Cl2) to give (4-(3,4-difluoro-2-(trifluoromethyl)phenyl) piperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) methanone (38) as a white solid (0.070 g, 66%): 1H NMR (500 MHz, CDCl3) δ7.36-7.31 (m, 1H), 7.12 (m, 1H), 4.82 (br, 1H), 4.38 (br, 1H), 4.11 (s, 2H), 4.09 (s, 2H), 3.24 (m, 2H), 2.89 (br, 1H), 1.93-1.68 (m, 4H); MS (ESI+) m/z 401 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[NH:11][N:10]=2)[CH3:8])=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl.C(N(CC)CC)C.[Cl:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1>ClCCl.CO>[Cl:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([CH:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH3:8])=[N:10][N:11]=2)=[CH:45][CH:44]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(c1ccncc1)c1n[nH]c(=O)c2ccccc12
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(c1ccncc1)c1nnc(Nc2ccc(Cl)cc2)c2ccccc12

Procedure:
A mixture of 300 mg (1.19 mmol) rac4-[1-(4-pyridyl)ethyl]-1(2H)-phthalazinone, 683 mg (4.77 mmol) phosphorus pentoxide, 657 mg (4.77 mmol) triethylamine hydrochloride, and 609 mg (4.77 mmol) 4-chloroaniline is heated for 8 h to 205° C. The brown solution is taken up in dichloromethane/methanol 19:1, washed successively with sat. Na2CO3 solution, 3× with water and brine, and the organic phase (Na2O4) is washed and concentrated by evaporation. Chromatography (SiO2; ethyl acetate/CH3OH, 19:1) yields the title compound: m.p.: 132-134° C.; Anal. calc.(C21H17N4Cl.½CH3OH) C, 68.52%; H, 5.08%; N, 14.87%; found C, 68.4%; H, 5.0%; N, 14.9%. The starting material is prepared as follows:
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNC(=O)c1ccccc1

Procedure:
(3-Amino-propyl)-carbamic acid tert-butyl ester (1.6 g) was treated with benzoyl chloride (1.1 eq.) and triethylamine (1.5 eq) in methylene chloride (50 mL). The reaction mixture was washed with 1 N HCl, sat, NaHCO3, and sat NaCl and the solvent removed to give product. LC-MS showed the product had the expected M+H+ of 279.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[OH-].[NH4+:14].C1COCC1>C(Cl)(Cl)Cl.CC(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:14])=[O:11]
Reactant: [NH4+]
Reactant: O=C(Cl)Cc1ccc(F)cc1Br
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: NC(=O)Cc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 2872.9 %

Procedure:
Combine (2-bromo-4-fluoro-phenyl)-acetyl chloride (3.5 g, 14 mmol), ammonium hydroxide (8.8 M in water, 50 mL, 0.45 mmol) and THF (10 mL) in a pressure vessel. Seal the vessel and stir the mixture overnight at RT. Dilute the mixture with chloroform-IPA (3:1, 100 mL). Wash the organic phase with aqueous saturated sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo to give the title compound as a white solid (3.0 g, 93%). MS (ES) m/z 232/234 [M+1]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:16])[CH:12]=2)[N:7]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][Br:17])[CH:12]=2)[N:7]=1
Reactant: Cc1ccc2nc(-c3cccs3)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nc(-c3cccs3)ccc2c1

Procedure:
11.9 g of 2-(2-thienyl)-6-methyl-quinoline together with 360 ml of carbon tetrachloride, 10.4 g of N-bromosuccinimide and 0.3 g of dibenzoyl peroxide are boiled for 15 hours under reflux. The reaction mixture is cooled and filtered off. Concentration of the filtrate yields 2-(2-thienyl)-6-bromomethyl-quinoline which melts at 95°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5](N[C@@H]2CCS(=O)(=O)C2)=[CH:6][CH:7]=1.[F:17][C:18]([F:23])([F:22])[CH2:19][CH2:20][NH2:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:21][CH2:20][CH2:19][C:18]([F:23])([F:22])[F:17])=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)ccc1N[C@@H]1CCS(=O)(=O)C1
Reactant: NCCC(F)(F)F
Product: Nc1cc(Cl)ccc1NCCC(F)(F)F

Procedure:
4-Chloro-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine was prepared in analogy to 4-chloro-N—((R)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-benzene-1,2-diamine in Example 2-1 by using 3,3,3-trifluoropropan-1-amine instead of (R)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-ylamine.
Reaction SMILES: [CH3:1][N:2]1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.Br[C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:42][C:43]2[CH:44]=N[C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]([CH3:57])[CH3:56])[CH2:51][CH2:50]3)=[CH:47][CH:48]=2)=[N:35][CH:34]=1.CC1(C)C(C)(C)OB([C:66]2[CH:67]=[C:68]3[C:72](=[CH:73][CH:74]=2)[C:71](=[O:75])[NH:70][CH2:69]3)O1>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH3:2].[CH:55]([N:52]1[CH2:51][CH2:50][N:49]([C:46]2[CH:1]=[CH:44][C:43]([NH:42][C:36]3[C:37]4[N:38]([N:39]=[CH:40][N:41]=4)[C:33]([C:66]4[CH:67]=[C:68]5[C:72](=[CH:73][CH:74]=4)[C:71](=[O:75])[NH:70][CH2:69]5)=[CH:34][N:35]=3)=[CH:48][CH:47]=2)[CH2:54][CH2:53]1)([CH3:56])[CH3:57]
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Reactant: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4ccc5c(c4)CNC5=O)n4ncnc34)cc2)CC1
Product: N
Yield: 53 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4 using 5-bromo-N-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine (0.6 g, 1.44 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one (0.56 g, 2.16 mmol) and Pd(PPh3)4 (0.416 g, 0.36 mmol) in 1.5M Na2CO3 (7.7 mL) and dioxane (23 mL). Purification by silica gel column chromatography eluting with DCM followed by 98:2 DCM:NH3 (7M in MeOH) affords the title compound (0.36 g, 53%) which is converted into the mesylate salt using 1M methanesulfonic acid in MeOH (0.77 mL). After trituration with diethyl ether and DCM the title compound is isolated as a solid (0.410 g). 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 1.35 (6H, d), 2.35 (3H, s, MsOH), 3.04 (2H, t), 3.20-3.27 (2H, m), 3.56-3.63 (3H, m), 3.89 (2H, d), 4.52 (2H, s), 7.09 (2H, d), 7.85 (1H, d), 7.95-8.01 (3H, m), 8.10 (1H, d), 8.24 (1H, s), 8.72 (1H, s), 8.74 (1H, s), 9.27 (1H, br s), 10.07 (1H, s). LCMS: Rt 2.93 min (97.9%), m/z (ES+) 469 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:16]3[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=3)=[CH:11][C:12]=2C(O)=O)=[CH:4][CH:3]=1.[C:23]([Cu])#[N:24].[N:26]1C2C(=CC=CC=2)C=C[CH:27]=1>Cl>[C:27]([C:19]1[CH:18]=[CH:17][C:16]([C:10]2[O:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([C:23]#[N:24])=[CH:7][CH:6]=3)=[CH:12][CH:11]=2)=[CH:21][CH:20]=1)#[N:26]
Reactant: N#C[Cu]
Reactant: c1ccc2ncccc2c1
Reactant: O=C(O)c1cc(-c2ccc(Br)cc2)oc1-c1ccc(Br)cc1
Agent: Cl
Product: N#Cc1ccc(-c2ccc(-c3ccc(C#N)cc3)o2)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of 2,5-bis(4-bromophenyl)-3-furan carboxylic acid 0.85 g (0.002 mole), CuCN 0.45 g (0.005 mole) in 10 ml freshly distilled quinoline is heated under reflux for 3 hours. The mixture is cooled and 100 ml dilute aqueous HCl is added and the mixture is stirred for 30 min. and filtered. The solid is washed with water and then with hexane. The resultant yellow solid is dissolved in acetone and passed through an alumina (neutral) column to yield a yellow crystalline solid 0.37 g (68%) having amp of 293°-295° C. The product is identical with that described in Example 1.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)(C#N)[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:23](=[O:26])(O)[O-:24].[Na+]>O>[N+:1]([C:4]1[C:9]2[NH:10][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)([C:23]([OH:24])=[O:26])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Temperature: 100 °C

Procedure:
5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carbonitrile (80 mg, 0.3 mmol) was dissolved in concentrated hydrochloric acid (3 mL, 100 mmol) and heated to 100° C. for 2 h. The reaction was allowed to cool to room temperature, diluted with water, and the pH was adjusted to pH 7 with sodium bicarbonate. The neutralized solution was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give crude 5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxylic acid as a solid (0.025 g. 30%). LCMS calculated for C14H12N3O5 (M+H)+: m/z=302.1. found: 301.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=[O:15])[C@@H:12]2[CH2:17][CH2:18][C@H:9]1[CH2:10][C@H:11]2[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25]([NH2:27])=[O:26].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[NH2:27][C:25]([C@@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:14]([C@@H:13]1[C@@H:12]2[CH2:17][CH2:18][C@@H:9]([CH2:10][C@H:11]2[OH:19])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])=[O:26]
Reactant: CC(C)(C)OC(=O)N1[C@H]2CC[C@H]([C@H](O)C2)[C@H]1C(=O)O
Reactant: NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H]2CC[C@H]([C@H](O)C2)[C@H]1C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid obtained in Example 2-5 (4.05 g), (2S)-2-pyrrolidinecarboxamide (1.77 g) and 1-hydroxybenzotriazole hydrate (1.68 g), were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.15 g) and N,N-diisopropylethylamine (5.2 mL) with cooling on an ice bath. After 5 minutes, the ice bath was removed and the mixture was stirred overnight at room temperature.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([CH:52]3[CH2:55][N:54]([CH3:56])[CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([CH:52]3[CH2:53][N:54]([CH3:56])[CH2:55]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CN(C)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 51.9 %

Procedure:
Following Example 148b, 482 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d and 350 mg 5-bromo-1-methyl-3-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)pyridin-2(1H)-one 172a, were reacted to give 213a as a yellow solid (324 mg, 52%). MS: [M+H]+ 625
Reaction SMILES: C([O-])([O-])=[O:2].[Na+].[Na+].OO.O.[CH3:10][O:11][CH:12]([O:22][CH3:23])[CH2:13][C:14]1[S:18][C:17]([CH3:19])=[N:16][C:15]=1[C:20]#[N:21]>CC(C)=O>[CH3:23][O:22][CH:12]([O:11][CH3:10])[CH2:13][C:14]1[S:18][C:17]([CH3:19])=[N:16][C:15]=1[C:20]([NH2:21])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: COC(Cc1sc(C)nc1C#N)OC
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(Cc1sc(C)nc1C(N)=O)OC
Reaction time: 2 h

Procedure:
2M Na2CO3-solution (64 ml, 127 mmol), H2O2 (30%, 43.3 ml, 424 mmol) and 45 ml water were placed and a solution of 5-(2,2-dimethoxy-ethyl)-2-methyl-thiazole-4-carbonitrile (4.5 g, 21 mmol) in 45 ml acetone was added dropwise at room temperature. The white suspension was stirred for 2 hrs. Acetone was evaporated and the aqueous residue was extracted three times with ethyl acetate. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product (4.8 g, 98%) was used without any further purification for the next step.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[OH-].[Na+]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:4]=3[CH2:3][CH:2]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C:8]=2[CH:9]=1
Reactant: Fc1ccc2c(c1)C(Cl)Cc1ccc(C(F)(F)F)cc1S2
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(C2Cc3ccc(C(F)(F)F)cc3Sc3ccc(F)cc32)CC1

Procedure:
9 G. of 10-chloro-8-fluoro-10,11-dihydro-3-trifluoromethyldibenzo[b,f]thiepin are treated with 11 g. of N-methylpiperazine and stirred for 10 minutes at 105°-110°C. The cooled mixture is treated with 2N sodium hydroxide and extracted with ether. The ether solution is washed neutral with water and shaken with dilute methanesulfonic acid. The acidic solution is made alkaline with sodium hydroxide and extracted with ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated in a vacuum, and there is obtained 1-{8-fluoro-10,11-dihydro-3-trifluoromethyl-dibenzo[b,f]thiepin-10-yl}-4-methylpiperazine as a yellow oil which is converted into the methanesulfonate having a melting point of 224°-226°C. by treatment with methanesulfonic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:4]([CH2:9][OH:10])[O:3]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[O:3][C@H:4]([CH2:9][O:10][S:13]([CH3:12])(=[O:15])=[O:14])[C@@H:5]([CH2:7][O:8][S:13]([CH3:12])(=[O:15])=[O:14])[O:6]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)O[C@H](CO)[C@@H](CO)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC1(C)O[C@H](COS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O1
Reaction time: 3 h
Yield: 66 %

Procedure:
The starting material (1) (3,4-O-isopropylidene-D-mannitol) was reacted with sodium periodate and potassium borohydride as described in J. Chem. Soc., Perkin Trans. I., 1972, 275 (the contents of which are herein incorporated by reference) to yield compound (2) in 92% yield. Compound (2) (5.1 g) was dissolved in pyridine (40 ml) and cooled in ice. To this solution was added methanesulphonyl chloride (18 ml), dropwise with stirring. The mixture was allowed to stand at room temperature for 3 hours, after which time it was added to a solution of sodium bicarbonate. This solution was then extracted with dichloromethane (5×50 ml) and the combined extracts were dried (MgSO4) and concentrated in vacuo. The residue obtained was recrystallised from ethanol to give 2,3-O-isopropylidene-1,4-di-O-methanesulphonyl-D-threitol (3), (6.6 g, 66%), m.p. 83°-85° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[Cl:13]Cl.O>C(O)(=O)C>[Cl:13][C:11]1[C:2]([OH:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:12])[CH2:5][CH2:4]2
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCc2c(ccc(Cl)c2O)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
16.4 Grams of 5-hydroxy-3,4-dihydrocarbostyril are dissolved in 300 ml of acetic acid. This solution is stirred at room temperature, and 50 ml of acetic acid solution containing 7 g of chlorine are added dropwise and the reaction is continued for 3 hours with stirring The reaction mixture is poured into 500 ml of water and allowed to stand for 1 hour and the precipitate thus formed is separated by filtration, washed with water and then dried. Recrystallization from ethanolwater obtains 13.5 g of 6-chloro-5-hydroxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 209°-210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1.[Cl:19][C:20]1[S:21][C:22]2[CH:28]=[C:27](I)[CH:26]=[CH:25][C:23]=2[N:24]=1.[F-].[Cs+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([C:8]3[N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:10]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=4)[CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: COc1ccc2ccn(C(=O)OC(C)(C)C)c2c1
Reactant: Clc1nc2ccc(I)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc2cc(-c3ccc4nc(Cl)sc4c3)n(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 83 %

Procedure:
tert-butyl 6-methoxy-1H-indole-1-carboxylate, from example 1BO, (2.50 g, 8.6 mmol) is dissolved in anhydrous dimethoxyethane (21.5 mL). To the solution is added 2-chloro-6-iodobenzothiazole (2.42 g, 8.2 mmol), cesium fluoride (2.53 g, 16.7 mmol) and PdCl2(PPh3)2 (0.23 g, 0.33 mmol). The reaction mixture is heated at reflux. After 17 h the reaction mixture is cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (4×20 mL). The extract is washed with saturated aqueous NaHCO3 (20 mL), dried over MgSO4 and concentrated under vacuum to give tert-butyl 2-(2-chlorobenzothiazol-6-yl)-6-methoxy-indole-1-carboxylate (2.95 g, 83%) as a hard foam.
Reaction SMILES: C(OC1C=C(C=CC=1O)CN1CCC(NC2C=C(C(F)(F)F)C(C(O)=O)=CN=2)CC1)C.Cl.Cl.C[O:35][C:36](=[O:54])[C:37]1[C:42]([C:43]([F:46])([F:45])[F:44])=[CH:41][C:40]([NH:47][CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[N:39][CH:38]=1.[CH2:55]([O:59][C:60]1[CH:61]=[C:62]([CH:65]=[CH:66][C:67]=1[O:68][CH3:69])[CH:63]=O)[CH:56]([CH3:58])[CH3:57]>>[CH2:55]([O:59][C:60]1[CH:61]=[C:62]([CH:65]=[CH:66][C:67]=1[O:68][CH3:69])[CH2:63][N:51]1[CH2:50][CH2:49][CH:48]([NH:47][C:40]2[CH:41]=[C:42]([C:43]([F:44])([F:45])[F:46])[C:37]([C:36]([OH:35])=[O:54])=[CH:38][N:39]=2)[CH2:53][CH2:52]1)[CH:56]([CH3:57])[CH3:58]
Reactant: COc1ccc(C=O)cc1OCC(C)C
Reactant: COC(=O)c1cnc(NC2CCNCC2)cc1C(F)(F)F
Agent: CCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(=O)O)cn3)CC2)ccc1O
Agent: Cl
Product: COc1ccc(CN2CCC(Nc3cc(C(F)(F)F)c(C(=O)O)cn3)CC2)cc1OCC(C)C

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic acid (example 201) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride (intermediate B7) and 3-isobutoxy-4-methoxy-benzaldehyde (intermediate E12) in a yield of 9.0 mg (12%). MS (ISP): 482.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
To a mixture of 5-fluoro-2-nitrophenol (50.0 g), potassium carbonate (44.0 g) and N,N-dimethylformamide (150 mL) was added under ice-cooling benzyl bromide (59.9 g), and the mixture was stirred at room temperature for 15 hr. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound (77.1 g, yield 98%) as pale-yellow crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1.[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1
Reactant: Cc1ccc(OCCCCl)cn1
Reactant: CN
Solvent: CO
Product: CNCCCOc1ccc(C)nc1
Temperature: 100 °C
Yield: 45.3 %

Procedure:
The 3-chloro-1-(6-methyl(3-pyridyloxy))propane (2.78 g, 18.3 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH was adjusted to 1 with 100% HCl solution and impurities were extracted with chloroform (4×25 mL). The pH of the aqueous phase was raised to 7 with 100% NaOH solution and other impurities were extracted with ether (4×30 mL). The aqueous layer was basified to pH 11 with 100% NaOH solution and extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.224 g (45.3%) of an oil.