Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[N:14]1[C:21]([Cl:22])=[N:20][C:18](Cl)=[N:17][C:15]=1[Cl:16]>CC(C)=O>[Cl:16][C:15]1[N:14]=[C:21]([Cl:22])[N:20]=[C:18]([O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:17]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Oc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(Oc2cccc3ccccc23)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 2 l round-bottom flask, 125.0 g of cyanuric chloride were dissolved in 300 ml of acetone, and a solution of 96.8 g of 1-naphthol in 300 ml of acetone was slowly added dropwise at 0° C. Subsequently, 168 ml of 4 N sodium hydroxide solution were slowly added dropwise. The mixture was stirred at 0° C. for 1 h, then warmed to room temperature and stirred for a further 1 h. The aqueous phase was removed and 200 ml of 5% NaOH and 200 ml of chloroform were added to the organic phase, the aqueous phase was removed again and the organic phase was washed twice with 80 ml each time of 5% NaOH and three times with 180 ml each time of water, and dried over sodium sulfate. The mixture was filtered and the solvent was distilled off under reduced pressure. The product was obtained as a colorless solid (preparation described in WO 8704321).
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=3)[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][C:34]([OH:38])([C:36]#[CH:37])[CH3:35]>[Cu]I.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.C1COCC1>[CH3:25][O:24][C:19]1[C:18]([NH:17][C:13]2[N:14]=[CH:15][N:16]=[C:11]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([C:37]#[C:36][C:34]([CH3:35])([OH:38])[CH3:33])[CH:10]=4)[CH:6]=[N:7]3)[N:12]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: C#CC(C)(C)O
Reactant: COc1ncccc1Nc1ncnc(-n2ncc3ccc(I)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ncccc1Nc1ncnc(-n2ncc3ccc(C#CC(C)(C)O)cc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a pressure tube was added 4-(6-iodo-1H-indazol-1-yl)-N-(2-methoxypyridin-3-yl)-1,3,5-triazin-2-amine (100 mg, 0.22 mmol), followed by triethylamine (0.7 mL) and THF (0.7 mL). Copper(I) iodide (4.28 mg, 0.022 mmol), PdCl2(PPh3)2 (15.76 mg, 0.022 mmol) and 2-methylbut-3-yn-2-ol (0.04 ml, 0.45 mmol) were then added and the reaction vessel was sealed and stirred at RT for 1 hr.
Reaction SMILES: [C:1]1([CH3:11])[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:1]1([CH3:11])[C:2]([S:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: N#Cc1ccc(CCCCO)cc1
Product: Cc1ccccc1S(=O)(=O)OCCCCc1ccc(C#N)cc1

Procedure:
The sub-title compound was prepared by addition of toluenesulphonyl chloride to 4-(4-hydroxybutyl)benzonitrile (see step (ii) above).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O-:14])=[O:13]>O1CCCC1>[CH:1]1([NH:4][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])(=[O:22])=[O:23])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of cyclopropylamine (1.0 g, 18 mmol) and triethylamine (3.7 mL, 27 mmol) in tetrahydrofuran (20 mL) was added 2-nitrobenzenesulfonyl chloride (3.9 g, 18 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hour. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The reaction solution was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and concentrated. The residue was washed with hexane and collected by filtration to obtain the title compound (3.7 g, 87%).
Reaction SMILES: [F:1][C:2]([F:43])([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=2[N+:26]([O-])=O)=[O:13])=[CH:6][CH:5]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:43])([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:33][CH:34]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=2[NH2:26])=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(CCOC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)c(N)c1
Yield: 71.5 %

Procedure:
5.11 g (8.38 mmol) of 2-(2,4-dinitrophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)-phenyl]methoxy}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethyl-formamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate is added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yielded 3.30 g of 2-(2,4-diaminophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate as yellow crystals. ES+=551 [M+H]; 19F NMR CD3CN 300 MHz; δ=−64.46, −67.44
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH:22]1([C:25]2([F:29])[CH2:28][NH:27][CH2:26]2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2([F:29])[CH2:28][N:27]([C:12]([C:10]3[CH:9]=[CH:8][C:7]([N:15]4[CH2:18][C:17]([F:20])([F:19])[CH2:16]4)=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[N:11]=3)=[O:14])[CH2:26]2)[CH2:24][CH2:23]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: FC1(C2CC2)CNC1
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC(F)(C2CC2)C1
Yield: 29.8 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 20 mg, 70.4 μmol) was reacted with 3-cyclopropyl-3-fluoroazetidine hydrochloride (CAN 936548-77-5, 12.8 mg, 84.4 μmol) to obtain the title compound (8 mg, 30%) as colorless liquid, MS (ESI): m/e=382.3 [MH+].
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([C:19]#[N:20])=[CH:15][N:14]=1)=[O:12])[CH3:9].Cl.[NH2:22][OH:23]>CCO>[NH2:20][C:19](=[N:22][OH:23])[C:16]1[N:17]=[CH:18][C:13]([C:11]([O:10][CH2:8][CH3:9])=[O:12])=[N:14][CH:15]=1
Reactant: CCOC(=O)c1cnc(C#N)cn1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnc(C(N)=NO)cn1
Temperature: 80 °C
Reaction time: 12 h
Yield: 62.1 %

Procedure:
Triethylamine (7.08 mL, 51.9 mmol) was added to a solution of 5-cyano-pyrazine-2-carboxylic acid ethyl ester (4.0 g, 22.6 mmol), hydroxylamine hydrochloride (3.45 g, 49.7 mmol) and EtOH (32 mL) and stirred at 80° C. for 12 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo and dissolved in H2O (30 mL). The aqueous solution was extracted with CHCl3 (3×30 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound (2.95 g, 62%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:17](Cl)[CH:18]1[O:22][CH2:21][CH2:20][CH2:19]1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:19][CH2:20][CH2:21][O:22]3)[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Reactant: ClCC1CCCO1
Product: CS(=O)(=O)c1cccc(C2CCN(CC3CCCO3)CC2)c1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and tetrahydrofurfuryl chloride, the titled compound was recovered by the procedure described in Example 1. MS m/z (relative intensity, 70 eV) 323 (M+, 1), 252 (bp), 129 (9), 115 (6), 70 (17). Rf=0.3 (MeOH, 0.03 (EtOAc).
Reaction SMILES: C([O:8][C:9](=[O:29])[CH:10]([NH:25][C:26](=[O:28])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:26]([NH:25][CH:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:17]=1)[C:9]([OH:29])=[O:8])(=[O:28])[CH3:27]
Reactant: [H][H]
Reactant: CC(=O)NC(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NC(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)O
Yield: 89 %

Procedure:
A suspension of rac.-2-acetamido-3-[4-((1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester (3.3 g, 8 mmol) and 10% Pd/C (320 mg) in ethanol (100 mL) was blanketed with hydrogen (1 atm) at room temperature. Upon the consumption of 1 equivalent of hydrogen, the mixture was filtered through celite. The celite pad was washed with ethanol (50 mL) and the filtrates were combined and concentrated. The resultant solid was purified by recrystallization from ethyl acetate/hexane to give rac.-2-acetamido-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid, (2.3 g. 7.4 mmol) in 89% yield, mp. 187°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1I.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:28]3[CH:29]=[C:24]([Cl:23])[CH:25]=[CH:26][C:27]=3[Cl:30])=[CH:16][CH:15]=2)[N:13]=1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: Clc1ccc(Cl)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2cc(Cl)ccc2Cl)cc1
Yield: 27.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 1,4-dichloro-2-iodobenzene (0.130 g, 0.470 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.040 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.50-7.72 (m, 7H), 7.82 (s, 1H), 8.05 (d, J=8.7 Hz, 2H), 12.75 (br s, 1H). MS (m/z): 458.31 (M+).
Reaction SMILES: [CH:1]([SiH:4]([CH:6]([CH3:8])[CH3:7])Cl)([CH3:3])[CH3:2].[Cl-].[NH4+].[CH3:11][CH2:12][CH2:13][CH2:14]C>C1COCC1>[CH2:11]([SiH:4]([CH:6]([CH3:8])[CH3:7])[CH:1]([CH3:3])[CH3:2])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC
Reactant: CC(C)[SiH](Cl)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[SiH](C(C)C)C(C)C
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Diisopropylchlorosilane (13.1 mL, 76.8 mmol) was dissolved in THF (75 mL), and n-butylmagnesium chloride THF solution (0.84M, 100 mL, 84 mmol) was added dropwise thereto in a nitrogen atmosphere for 10 minutes. Subsequently, cuprous bromide (286 mg, 2.00 mmol) was added to the resultant mixture, followed by stirring at 65° C. for 8 hours. The reaction mixture was left to cool, and saturated aqueous ammonium chloride and n-pentane were added thereto. The formed organic layer was washed three times with water and once with saturated brine, and the thus-washed layer was dried over sodium sulfate anhydrate. The solvent was removed, followed by purification through distillation under reduced pressure, whereby the Compound 47a was obtained as a colorless liquid (boiling point; 50 mmHg, 93.2 to 95.5° C. fraction, 8.43 g, 64%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:25])([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[CH:14]([F:16])[F:15]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:22][C:21]1[CH:20]=[CH:19][C:18]([O:17][C:13]([F:12])([F:25])[CH:14]([F:15])[F:16])=[CH:24][CH:23]=1)=[O:9]
Reactant: Nc1ccc(OC(F)(F)C(F)F)cc1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)C(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 169.2 using 5-bromo-6-chloro-nicotinic acid and 4-(1,1,2,2-tetrafluoroethoxy)aniline to afford a solid. UPLC-MS (Condition 3), tR=1.2 min, m/z=424.9 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH2:49])=[CH:47][CH:48]=1)=[O:42])[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH:34]2[CH2:40][CH2:39][CH:38]1[CH2:37][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH:49][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:25])[CH3:1])[N:14]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=5)[C:8]=4[N:9]=3)=[CH:47][CH:48]=1)=[O:42])[CH2:35]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1-c1cccc(C(C)(C)C)c1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1-c1cccc(C(C)(C)C)c1
Yield: 63.5 %

Procedure:
Following general N—C coupling procedure 1, 7-(3-tert-Butyl-phenyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.280 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (93 mg, 0.280 mmol, 1.0 eq) to give 3-{6-[7-(3-tert-Butyl-phenyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (116 mg) in 60% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 9H) 1.43 (s, 9H) 1.59 (br. s., 2H) 1.81 (br. s., 2H) 2.86 (br. s., 3H) 2.94 (br. s., 3H) 4.12 (br. s., 2H) 6.91 (s, 1H) 7.37-7.43 (m, 2H) 7.45-7.58 (m, 2H) 7.67 (dd, J=8.84, 2.27 Hz, 1H) 8.32 (dd, J=5.81, 2.78 Hz, 2H) 8.96 (s, 1H) 10.05 (s, 1H). MS m/z 653.7 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:33])[N:20]([CH:24]5[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=O)[CH2:26][CH2:25]5)[C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:36]([F:39])([F:38])[F:37])[CH:4]=1.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42]>>[CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:33])[N:20]([CH:24]5[CH2:25][CH2:26][CH:27]([C:30]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:32])[CH2:28][CH2:29]5)[C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:36]([F:37])([F:39])[F:38])[CH:4]=1
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(C5CCC(C(=O)O)CC5)C4=O)ccc32)c(C(F)(F)F)c1
Reactant: CS(N)(=O)=O
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(C5CCC(C(=O)NS(C)(=O)=O)CC5)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
4-[(5Z)-5-({1-[4-Methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(methylsulfonyl)cyclohexanecarboxamide was prepared from 4-[(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]cyclohexanecarboxylic acid (Example 22) following General Procedure L using methanesulfonic acid amide in place of the sulfamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.Cl.[NH2:13][C@H:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[NH:19][C:20](=[O:31])[C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[O:29][CH3:30].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:30][O:29][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=1[C:20]([NH:19][C@H:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[NH:13][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1)=[O:31]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1

Procedure:
A mixture of 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 266 mg, 1.46 mmol), N-[(1S,2S)-2-aminocyclopentyl]-2,6-dimethoxybenzamide hydrochloride (Intermediate 5; 400 mg, 1.33 mmol), DIPEA (0.70 ml, 3.99 mmol) and DMSO (4.8 ml) was subjected to microwave irradiation at 140° C. for 2 hours. Upon cooling, the resulting mixture was partitioned between ethyl acetate (10 ml) and water (10 ml) and the combined organics were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was further purified by trituration with di-isopropylether to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Yield: 80.4 %

Procedure:
A mixture of 4.7 g of (S)α-cyano-3-phenoxy-benzyl (IR,cis) 2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate in 45 ml of ethyl acetate was hydrogenated in the presence of 500 mg of 10% palladium hydroxide on barium sulfate and 6.5 ml of quinoline and the mixture was filtered. The filtrate was washed with N hydrochloric acid, then with water until neutral, dried and evaporated to dryness. The 5.1 g of oil residue were chromatographed over silica gel and eluted with a 70-30-1 mixture of hexane-ethyl acetate-acetic acid to obtain 3.8 g of (S)α-cyano-3-phenoxy-benzyl (IR,cis) 2,2-dimethyl-3-[(Z) 3-hydroxy-3-oxo-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5](Br)=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(N)ncc2Br)CC1
Reactant: COc1ccc(B(O)O)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: CC#N
Product: COc1ccc(-c2cnc(N)cc2NCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 150 °C
Yield: 149.2 %

Procedure:
Two capped 0.5 mL microwave reaction vials each containing a solution of tert-butyl 4-((2-amino-5-bromopyridin-4-ylamino)methyl)piperidine-1-carboxylate (30 mg, 0.078 mmol), 4-methoxyphenyl boronic acid (17.8 mg, 1.5 eq.), Pd(PPh3)4 (4.5 mg, 5 mol %), 0.5M aqueous sodium carbonate (0.23 mL, 1.5 eq.) in acetonitrile (0.78 mL) were heated at 150° C. for 20 min by microwave irradiation. After cooling, the contents of the two reaction vials were combined and solvents were removed in vacuo. The crude product was purified by chromatography using a Biotage SNAP silica (10 g) column, eluting with a gradient of methanol/NH3 (99/1) in dichloromethane, to give the title compound as a yellow solid (48 mg, 75%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[OH:11][C:12]1[CH:24]=[CH:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH:13]=1>>[CH:13]1[C:14]2[NH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]=2[CH:23]=[CH:24][C:12]=1[O:11][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Reactant: CCOC(=O)CCCCBr
Product: CCOC(=O)CCCCOc1ccc2c(c1)[nH]c1ccccc12
Yield: 34.3 %

Procedure:
In a manner analogous to that of example 6(a), ethyl 5-bromo-pentanoate (685 mg, 3.28 mmol) was reacted with 2-hydroxycarbazole (600 mg, 3.28 mmol) to give ethyl 5-(9H-carbazol-2-yloxy)-pentanoate (350 mg, 34%) as a colorless solid. MS (MH+)310.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:9]([NH:11][CH:12]2[CH2:17][C:16](=[O:18])[CH2:15][CH2:14][CH:13]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.CO.[BH4-].[Na+]>COCCOC>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:35][CH2:36]2)[C:9]([NH:11][CH:12]2[CH2:17][CH:16]([OH:18])[CH2:15][CH2:14][CH:13]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[O:10])[CH2:2][CH2:3]1
Reactant: COc1ccc(C2CCC(=O)CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COc1ccc(C2CCC(O)CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Yield: 87.8 %

Procedure:
7.2 g of (±)-3,4-bis-cyclopropylmethoxy-N-[(1RS,2RS)-2-(3,4-dimethoxyphenyl)-5-oxo-cyclohexyl]benzamide (compound C1) are dissolved in 550 ml of 1,2-dimethoxyethane and 34 ml of methanol and treated portionwise with 600 mg of sodium borohydride at room temperature. The reaction mixture is concentrated, the residue redissolved in ethyl acetate and extracted with water. The organic layer is dried using sodium sulfate, concentrated and the residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 6/3/1. 6.35 g of the title compound are obtained.
Reaction SMILES: C([O:5][C:6](=[O:20])[NH:7][CH:8]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)[CH2:9]O)(C)(C)C.[H-].[Na+]>C1COCC1>[F:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[F:18])[CH2:11][CH:8]1[CH2:9][O:20][C:6](=[O:5])[NH:7]1
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccc(F)c(F)c2)CO1
Reaction time: 3 h
Yield: 37.5 %

Procedure:
A solution of (+)-[1-(3,4-difluorobenzyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester (1.00 g, 4.00 mmol) in THF (10 mL) was added via a dropping funnel to a stirring suspension of 95% NaH (0.12 g, 5.0 mmol) in THF (20 mL) at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with water (10 mL). The biphasic mixture was extracted with Et2O (50 mL), washed with brine, filtered and the solvent was removed, in vacuo. The resulting gummy residue was purified by column chromatography (Rf=0.25, 3:2 hexane-EtOAc), to give the desired product as a white solid (0.320 g, 76%).