Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16](Cl)(=[O:18])=[O:17])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH:30]=[CH:31][C:32]#[N:33])(=[O:29])=[O:28])=[CH:23][CH:22]=1.N1C=CC=CC=1>O1CCOCC1>[CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH:30]=[CH:31][C:32]#[N:33])(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:18])=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)Nc2ccc(S(=O)(=O)C=CC#N)cc2)c(C(C)C)c1

Procedure:
a solution of 9.1 g (0.03 mol) of 2,4,6-tri-isopropylbenzenesulfonyl chloride in 50 ml dioxane is added at room temperature to a solution of 6.3 g (0.03 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile in 150 ml dioxane, the dioxane solution additionally containing 3 ml (0.03 mol) of pyridine. After 8 hours the reaction mixture is filtered and evaporated and a tannish solid consisting of 3-[4-(2,4,6-tri-isopropylbenzenesulfonamido)benzenesulfonyl]acrylonitrile is obtained: ##SPC19##
Reaction SMILES: C([O:4][C@@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][C:9]2[C:20]3[C:25]([CH:26]=[CH:27][C:8]=2[N:7]([CH2:28][CH2:29][NH:30][CH3:31])[C:6]1=[O:32])=[CH:24][CH:23]=[CH:22][CH:21]=3)(=O)C.[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>C(O)C.C([O-])([O-])=O.[K+].[K+].C(#N)C>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[OH:4][C@@H:5]1[C@H:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[S:10][C:9]2[C:20]3[C:25]([CH:26]=[CH:27][C:8]=2[N:7]([CH2:28][CH2:29][NH:30][CH3:31])[C:6]1=[O:32])=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: CNCCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(OC)cc2)Sc2c1ccc1ccccc21
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CNCCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2c1ccc1ccccc21
Yield: 53.5 %

Procedure:
A solution of 0.4 g (0.00089 mol) of (+)-cis-3-(acetyloxy)-2,3-dihydro-2-(4-methoxyphenyl)-5-[2-(methylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one in a mixture of 10 ml of ethanol and 10 ml of 0.5M K2CO3 was heated at 70°-80° for one hour. The mixture was concentrated to a low volume under reduced pressure, diluted with water (saturated with NaCl) and extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (MgSO4) and the solvent was removed. The residue, 0.25 g in acetonitrile, was treated with 0.08 g (0.0069 mol) of fumaric acid and the crystals were collected to afford 0.25 g (53%) of (+)-cis-2,3-dihydro-3-hydroxy-5-[2-(methylamino)ethyl]-2-(4-methoxyphenyl)naphtho[1,2-b][1,4]thiazepin-4(5H)-one (E)-2-butenedioate as the semihydrate, mp 178°-180° [α]D 25 +7.97° (C. 0.966, MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C:8](=O)[CH:9]([F:11])[F:10])[CH:7]=1.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>O1CCCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6](/[C:8](=[N:20]\[S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])/[CH:9]([F:11])[F:10])[CH:7]=1
Reactant: O=C(c1cc(Br)ccc1F)C(F)F
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)/N=C(\c1cc(Br)ccc1F)C(F)F
Temperature: 70 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 1-(5-bromo-2-fluorophenyl)-2,2-difluoroethanone (intermediate E1.1) (13.2 g, 52.2 mmol) and (S)-(−)-2-methyl-2-propanesulfinamide (6.96 g, 57.4 mmol) in tetrahydrofuran (104 ml) was added at 23° C. titanium(IV) ethoxide (21.4 g, 19.5 ml, 93.9 mmol). The yellow solution was stirred at 70° C. for 3 hours. The cooled reaction mixture was poured into ice water, diluted with ethyl acetate and filtered through a pad of Dicalite. The organic layer was separated and washed with brine and then dried over Na2SO4. Removal of the solvent in vacuum left a yellow oil (18.25 g), which was purified by silica column chromatography 200 g, SiO2 with dichloromethane/heptane 1:1 to give (S,E)-N-(1-(5-bromo-2-fluorophenyl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (14.49 g, 40.7 mmol, 78.0% yield) as a yellow oil. MS (ISP): m/z=355.9 [M+H]+ and 357.9 [M+2+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([O:36]C)=[O:35])=[O:31])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.[OH-].[Na+].Cl>CO>[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)CNC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)NCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-methyl 2-(3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanamido)acetate 2,2,2-trifluoroacetate (18 mg, 0.034 mmol) in MeOH (0.5 mL) was added 5M sodium hydroxide (0.048 mL, 0.241 mmol). The reaction was stirred at room temperature overnight. The mixture was added 1M HCl (2 mL) and purified by HPLC to give the title compound. LCMS m/z=395.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.CCCCCC.C([Li])CCC.[B:28](OC)([O:31]C)[O:29]C.S(=O)(=O)(O)O>C1COCC1>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:4]2[CH:3]=[C:2]([B:28]([OH:31])[OH:29])[CH:7]=[CH:6][CH:5]=2)=[CH:10][CH:11]=1)[CH3:16]
Reactant: CCc1ccc(Cc2cccc(Br)c2)cc1
Reactant: COB(OC)OC
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cccc(B(O)O)c2)cc1
Reaction time: 0.33 h
Yield: 31.6 %

Procedure:
In a nitrogen stream, a solution of 1-bromo-3-(4-ethylbenzyl)benzene (2.19 g, 7.96 mmol) in THF (20 mL) was cooled to −78° C., and an n-butyllithium hexane solution (2.44 M, 3.42 mL) was added dropwise thereto and the mixture solution was stirred at the same temperature for 20 minutes. After addition of trimethyl borate (2.68 mL, 23.87 mmol), the reaction mixture was stirred at the temperature for five minutes and at room temperature for 12.5 hours. After cooling the reaction mixture in an ice bath, concentrated sulfuric acid (10 mL) was added dropwise thereto and the mixture solution was stirred at the same temperature for one hour. The mixture was extracted with ether and the organic layer was washed with water and then dried over sodium sulfate. To a white solid obtained by distilling the solvent under reduced pressure was added hexane-ethyl acetate (10:1)(5 mL), the mixture was filterated and then the obtained solid was washed with hexane-ethyl acetate (10:1). The obtained white powder was dried under reduced pressure to obtain the title compound (604.2 mg, 32%).
Reaction SMILES: C([O-])=O.[NH4+].[CH:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)([CH3:7])[CH3:6]>CO.[Pd]>[CH:5]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:7])[CH3:6]
Reactant: CC(C)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)Nc1ccccc1N
Temperature: 25 °C
Yield: 87.4 %

Procedure:
Ammonium formate (960 mg, 15.0 mmol) is added to a solution of N-isopropyl-2-nitroaniline (550 mg, 3.03 mmol) in methanol. This may be followed by a catalytic amount of palladium on carbon (5%). The mixture may be refluxed overnight, cooled to room temperature and filtered. The filtrate may be concentrated by any applicable and the residue may be purified, for example by Biotage column chromatography to give N1-isopropylbenzene-1,2-diamine (398 mg)
Reaction SMILES: C[CH2:2][N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)C=C(NC)[N:12]=1.C(=O)C.C([BH3-])#N>CO.C(O)(=O)C>[Cl:10][C:11]1[C:20]2[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2)[CH:9]=[C:7]([N:3]([CH2:4][CH3:6])[CH3:2])[N:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1cc2cc(OC)ccc2c(Cl)n1
Agent: CC=O
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: CCN(C)c1cc2cc(OC)ccc2c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
Hunig's base (0.235 mL, 1.347 mmol) was added to a solution of 1-chloro-6-methoxy-N-methylisoquinolin-3-amine (150 mg, 0.674 mmol) and acetaldehyde (0.042 mL, 0.741 mmol) in MeOH (5 mL) and stirred for 30 min Acetic Acid (1 mL) and Cyanoborohydride, polymer supported (2 mmol/gram) (50 mg, 0.674 mmol) were then added and the reaction stirred at r.t. for 2 hrs. Reaction filtered through nylon frit filter and evaporated on rotovap to give the crude product with no purification. The material was taken up in EtOAc and washed with sat. sodium bicarbonate. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the expected product 1-chloro-N-ethyl-6-methoxy-N-methylisoquinolin-3-amine (140 mg, 83% yield) as a dark orange solid. MS: MS m/z 251.15(M++1).
Reaction SMILES: [CH2:1]([C:4]1C=CN=C(C#N)C=1)[CH2:2]C.[C:12]([C:15]1[CH:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1)(=[O:14])[CH3:13]>>[C:12]([C:15]1[CH:20]=[C:19]([CH2:2][CH2:1][CH3:4])[CH:18]=[CH:17][N:16]=1)(=[O:14])[CH3:13]
Reactant: CCCc1ccnc(C#N)c1
Reactant: CC(=O)c1cc(Cl)ccn1
Product: CCCc1ccnc(C(C)=O)c1

Procedure:
The title compound was prepared from 4-propyl-2-pyridinecarbonitrile according to the procedure for preparing 2-acetyl-4-chloropyridine described in Example 33.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:24])([CH2:22][CH3:23])[CH2:20][OH:21]>>[OH:21][CH2:20][C:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:24])[CH2:22][CH3:23]
Reactant: CCC(C)(N)CO
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: CCC(C)(CO)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 8e, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and 2-amino-2-methyl-1-butanol (CAN 10196-30-2, 64.74 mg, 0.64 mmol) as starting materials, and isolated (12 mg, 8.79%) as off white solid, LC-MS (UV peak area, ESI) 100%, 320.4 (M+H).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[C:13]12([NH:23][OH:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>>[C:13]12([N+:23]([O-:24])=[CH:1][C:3]3[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=3)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Reactant: ONC12CC3CC(CC(C3)C1)C2
Agent: [Na]
Product: O=S(=O)(O)c1ccc(C=[N+]([O-])C23CC4CC(CC(C4)C2)C3)o1
Yield: 59 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-adamantylhydroxylamine, the title compound was prepared in 59% yield as the sodium salt, m.p. 236.9° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[C:31]([O:38][CH3:39])[CH:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:33]1[CH:34]=[C:29]([CH3:28])[CH:30]=[C:31]([O:38][CH3:39])[CH:32]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: COc1cc(C)ccc1B(O)O
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C)cc(OC)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 4-methyl-2-methoxylphenylboronic acid (92 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate and concentrated to yield a yellow oil which was purified by flash column eluted with 30% ethyl acetate in hexane, then recrystallization from ethyl ether to yield 4-(3-methoxy-5-methyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>O1CCOCC1>[NH:12]([C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: NN
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc(C(=O)O)ccn1
Temperature: 100 °C
Yield: 4.2 %

Procedure:
To a solution of 2-chloropyridine-4-carboxylic acid (1.57 g, 100 mmol) in 1,4-dioxane (30 mL) was added hydrazine hydrate (1.0 g, 200 mmol) dropwise at rt. The reaction mixture was heated at 100° C. overnight. The mixture was concentrated, and the residue was purified by flash column chromatography (CH2Cl2/MeOH=20/1) to afford the title compound (650 mg, 42%) as a white solid. [M+H] Calc'd for C6H7N3O2, 154; Found, 154.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH2:22][OH:23])=[CH:17][C:16]=2[CH3:24])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[OH-].[Na+].[CH2:28]1COCC1>>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:16]([CH3:24])=[CH:17][C:18]([CH2:22][O:23][CH3:28])=[CH:19][C:20]=2[CH3:21])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(CO)cc2C)c1C
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(COC)cc2C)c1C
Reaction time: 0.08 h

Procedure:
To a solution of {4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-methanol in dry THF was added 60% NaOH in oil and stirred for 5 min. Excess of Mel was added and stirred at room temperature for 2 hr. After standard worked up procedure and purification, the title compound was obtained as a clear golden oil. 1H NMR(CDCl3) d 7.02(s,2H), 6.06(s,1H), 4.40(s,3H), 3.72(d,1H), 3.39(s,3H), 3.36(m,1H), 2.12(s,3H), 2.11(s,3H), 2.10(s,6H), 1.4-1.7(m,4H), 0.95(t,6H) ppm.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]2[NH:8][C:9]([C:11]3[CH:12]=[C:13]([C:29](O)=[O:30])[CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=[CH:20][C:19]=4[OH:28])[C:16]=3[OH:17])=[N:10][C:6]=2[CH:5]=1)(=[NH:3])[NH2:2].[NH2:34][CH2:35][CH2:36][S:37]([O-:40])(=[O:39])=[O:38].[Li+]>>[C:1]([C:4]1[CH:33]=[CH:32][C:7]2[NH:8][C:9]([C:11]3[CH:12]=[C:13]([C:29]([NH:34][CH2:35][CH2:36][S:37]([OH:40])(=[O:39])=[O:38])=[O:30])[CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=[CH:20][C:19]=4[OH:28])[C:16]=3[OH:17])=[N:10][C:6]=2[CH:5]=1)(=[NH:3])[NH2:2]
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(C(=O)O)cc(-c4cc(S(N)(=O)=O)ccc4O)c3O)nc2c1
Reactant: NCCS(=O)(=O)[O-]
Agent: [Li+]
Product: N=C(N)c1ccc2[nH]c(-c3cc(C(=O)NCCS(=O)(=O)O)cc(-c4cc(S(N)(=O)=O)ccc4O)c3O)nc2c1

Procedure:
Proceeding as in Example 17, but substituting 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carboxylic acid (20 mg, 40 μmol), prepared as in Reference 10, and lithium 2-aminoethanesulfonate, prepared as in Reference 4, gave 2-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-ethanesulfonic acid as a yellow solid, Compound 111. RP-HPLC (1-90S) RT=2.21 min; 1H NMR (400 MHz, d6-DMSO, selected signals): δ 9.36* (2H, s), 8.98* (2H, s), 8.74(1 H, J=1.6 Hz), 8.74 (1H, d, J=2.0 Hz), 8.49* (1H, br t, J=5.0 Hz), 8.17 (1H, s), 7.85 (1H, d, J=8.4 Hz), 7.81 (1H d, J=2.0 Hz), 7.75 (1H, dd, J=8.4 Hz, 0.8 Hz), 7.70 (1H, dd, J=2.4 Hz), 7.67 (1H, dd, J=8.4, 2.4 Hz); 7.16* (2H, br s), 7.07 (1H, d, J=8.4 Hz); m/z (LCMS-ESI): Q+575 (M+H); Q−573 (M−H).
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[N:23]=[C:22]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:21]=3)=[CH:16][CH:15]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1>>[CH:27]([O:26][C:24]1[N:23]=[C:22]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:21]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:12]([NH:11][C:9]3[CH:10]=[CH:2][C:3]([C:4]([NH:37][CH:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)=[O:6])=[CH:7][CH:8]=3)=[O:36])=[CH:15][CH:16]=2)[N:25]=1)([CH3:28])[CH3:29]
Reactant: Cc1cc(NC(=O)Nc2ccc(-c3nc(OC(C)C)nc(N4CCOCC4)n3)cc2)ccc1C(=O)O
Reactant: CN1CCC(N)CC1
Product: CC(C)Oc1nc(-c2ccc(NC(=O)Nc3ccc(C(=O)NC4CCN(C)CC4)cc3)cc2)nc(N2CCOCC2)n1
Yield: 27 %

Procedure:
Starting from methyl 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid (200 mg, 0.42 mmol) and 4-amino-1-methylpiperidine following the procedure as outlined in Experimental 71, 65 mg (27% Yield) of the titled compound was isolated as white solid. MS (ESI) m/z 574.68.
Reaction SMILES: [C:1]([C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]([CH:18]=[O:19])[C:9]([CH:15]([CH3:17])[CH3:16])=[N:10][C:11]=1[CH:12]([CH3:14])[CH3:13])(OCC)=[O:2].[CH2:27]([Li])[CH2:28][CH2:29][CH3:30]>C(OCC)(=O)C.CCCCCC>[CH:15]([C:9]1[C:8]([CH2:18][OH:19])=[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:6]([CH:1]([OH:2])[CH2:27][CH2:28][CH2:29][CH3:30])=[C:11]([CH:12]([CH3:13])[CH3:14])[N:10]=1)([CH3:17])[CH3:16]
Reactant: [Li]CCCC
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCC(O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and n-butyllithium, according to the procedures described in Example 93. 1H NMR (300 MHz, CDCl3): δ 7.16 (m, 4 H), 4.49 (m, 1 H), 4.31 (d, J=5.5 Hz, 2 H), 3.74 (septet, J=6.6 Hz, 1 H), 3.42 (septet, J=6.6 Hz, 1 H), 1.88 (m, 1 H), 1.58 (d, J=3.3 Hz, 1 H), 1.18 (m, 18 H), 0.821 (t, J=4.1 Hz, 3 H). FAB-MS: calcd for (C23H32NFO2) 373, found 374 (M+H). Anal. Calcd for C23H32NO2F: C, 73.96; H, 8.64; N, 3.75; F, 5.09. Found: C, 73.81; H, 8.60; N, 3.58; F, 5.02. mp 166-168° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: [CH:1]([C:4]([CH:15]([CH3:17])[CH3:16])=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[O:6][CH3:7])([CH3:3])[CH3:2].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.C(N(CC)CC)C>[C:18]([O:14][C:10]1[CH:9]=[C:8]([C:5]([O:6][CH3:7])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:15]([CH3:17])[CH3:16])[CH:13]=[CH:12][CH:11]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=C(C(C)C)C(C)C)c1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=C(C(C)C)C(C)C)c1cccc(OC(=O)c2ccccc2)c1
Reaction time: 1 h

Procedure:
Alkene 1b (4.5 g, 1.9 mmol) was dissolved in 50 mL of dry CH2Cl2 with 5.3 mL of anhydrous triethylamine. The flask was purged with argon and cooled in an ice bath. Benzoyl chloride (4.05 g, 2.9 mmol) was added dropwise. The cooling bath was removed and stirring continued for 1 hour at room temperature. The mixture was filtered and the solution was washed with water, dried over MgSO4 and evaporated. The residue was suspended in hexane, the solid filtered away and the solution evaporated. The residue was purified by column chromatography on silica gel, eluting with 1% ethyl acetate in hexane yielding 3.7 g of dioxetane 1d: 1H NMR (CDCl3) δ 8.25-7.05 (m, 9H), 3.25 (s, 1H), 2.54 (sept, 1H, J=6.9 Hz), 2.40 (sept, 1H, J=6.9 Hz), 2.29 (s, 3H), 1.26 (d, 6H, J=6.9 Hz), 0.95 (d, 6H, J=6.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:31]=[CH:30][C:23]([C:24]([NH:26][CH2:27][CH2:28][OH:29])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([F:32])[CH:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][CH2:28][OH:29])=[O:25])=[CH:30][CH:31]=2)[CH2:9]/[C:10](=[N:34]\[OH:35])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([F:32])[CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NCCO)cc2)c2ccc(Cl)cc2F)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NCCO)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-[1-(4-chloro-2-fluoro-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-N-(2-hydroxy-ethyl)-benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless foam containing 7% of the corresponding Z isomer, MS (ESI+): m/z=472.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[H-].[Na+].[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21]>CN(C)C=O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccc(C(F)(F)F)c1
Yield: 52.9 %

Procedure:
Using 0.24 g of 3-(trifluoromethyl)benzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.17 g of 2-(3-(trifluoromethyl)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (36)).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)([O-])=O>CCOC(C)=O.[Pd]>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=2[CH:6]=[N:7]1
Reactant: O=[N+]([O-])c1cccc2c1cnn2C1CCCCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc2c1cnn2C1CCCCO1
Reaction time: 22 h
Yield: 96.7 %

Procedure:
A solution of 4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.05 g, 4247 μmol) in EtOAc (100 mL) was treated with 10% Pd/C (60 mg) and stirred under an atmosphere of H2. The reaction was monitored by LCMS and found to be complete after 22 h. The reaction was filtered and concentrated (caution: tends to foam/bump). The residue was triturated with Et2O to give 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (892 mg, 96.7% yield) as an off-white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.11 (s, 1H); 7.03 (t, J=7.82 Hz, 1H); 6.74 (d, J=8.22 Hz, 1H); 6.18 (d, J=7.43 Hz, 1H); 5.78 (s, 2H); 5.59-5.67 (m, 1H); 3.82-3.92 (m, 1H); 3.63-3.74 (m, 1H); 2.30-2.45 (m, 1H); 1.96-2.08 (m, 1H); 1.84-1.94 (m, 1H); 1.65-1.80 (m, 1H); 1.55 (br. s., 2H). m/z (ESI, +ve). Found 218 (M+H)+.