Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[O:9]([C:11]1[C:16]([Br:17])=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[N:12]=1)[CH3:10].Cl[P:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C1COCC1>[CH3:10][O:9][C:11]1[C:16]([Br:17])=[C:15]([P:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=[C:13]([O:18][CH3:19])[N:12]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: COc1ccc(Br)c(OC)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(P(c2ccccc2)c2ccccc2)c(Br)c(OC)n1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a magnetically stirred solution of 4.0 mL of approximatly 2.0M LDA solution (in hexane) (7.98 mmol) was added a solution of 2,6-dimethoxyl-3-bromopyridine (3.14 g, 6.14 mmol) in 10 mL of THF at -78° C. over a period 20 minutes while the internal temperature was kept below -78° C. To the resulting red-brown suspension was added a solution of chlorodiphenylphosphine (1.20 mL, 6.75 mmol) in the 10 mL of THF at -78° C. The reaction mixture was allowed to warm to ambient temperature overnight and was poured into 20 mL water. The organic product was extracted with dichloromethane (3×20 mL). The combined extract was dried with anhydrous magnesium sulfate and was concentrated in vaccuo to give a crude product which was recrystallized in methanol to give 2.34 g of pure product (95% theoretical yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:9]=[CH:10][C:11]2[CH:17]=[C:16]([C:18]3[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=3[Cl:29])[C:15](=[O:30])[N:14]([CH2:31][CH3:32])[C:12]=2[N:13]=1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:45])[CH:43]=[CH2:44]>ClCCl>[Cl:24][C:23]1[C:22]([O:25][CH3:26])=[CH:21][C:20]([O:27][CH3:28])=[C:19]([Cl:29])[C:18]=1[C:16]1[C:15](=[O:30])[N:14]([CH2:31][CH3:32])[C:12]2[N:13]=[C:8]([NH:7][C@@H:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[NH:1][C:42](=[O:45])[CH:43]=[CH2:44])[N:9]=[CH:10][C:11]=2[CH:17]=1
Reactant: CCn1c(=O)c(-c2c(Cl)c(OC)cc(OC)c2Cl)cc2cnc(N[C@@H]3CCC[C@@H]3N)nc21
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1CCC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)c(=O)n(CC)c2n1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 2-(((1R,2S)-2-aminocyclopentyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one (0.105 mmol) in dichloromethane (2.1 mL) at −20° C. was added DIEA (0.018 mL, 0.105 mmol) and acryloyl chloride (0.008 mL, 0.105 mmol) and the reaction was stirred for 1 h. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2R)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)acrylamide (36 mg, 65%). MS (ES+) C25H27Cl2N5O4 requires: 531, found: 532.
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][S:8]([C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])(=[O:10])=[O:9])=[O:5])C.[NH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][NH:24][C:12]([C:11]([S:8]([CH2:7][CH:6]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:4]([OH:5])=[O:3])(=[O:10])=[O:9])([CH3:16])[CH3:15])=[O:13]
Reactant: NCCOCCO
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)O
Product: CC(C)(C(=O)NCCOCCO)S(=O)(=O)CC(Cc1ccccc1)C(=O)O

Procedure:
In an analogous manner to that described in Example 6, paragraphs (a) to (c), starting from 2-mercaptoisobutyric acid and ethyl 2-benzylacrylate there was obtained (RS)-2-[[2-[(ethoxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionic acid, reaction of which 2-(2-aminoethoxy)ethanol and subsequent enzymatic hydrolysis of the resulting ethyl ester yielded (S/R=9/1 )-α-[[[1-[[2-(2-hydroxyethoxy)ethyl]carbamoyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamic acid, MS: 401.9 (M+H)+, as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)([OH:15])[CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)([OH:15])[CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCOC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Yield: 100 %

Procedure:
A solution of (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-2-(2-methoxyethoxy)-ethyl)piperidine-1-carboxylate (30 mg, 0.073 mmol) in 20% TFA/CH2Cl2 (5 mL) was stirred at 0° C. for 30 min. Evaporation of the solvent afforded (1S)-1-(3-chlorophenyl)-2-(2-methoxy-ethoxy)-1-((3R)-piperidin-3-yl)ethanol (30 mg, 0.073 mmol 100%). MS (E/Z): 314 (M+H+).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:39]=[CH:40][CH:41]=1)[O:23][C:24]1[CH:38]=[CH:37][C:27]2[N:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[S:30][C:26]=2[CH:25]=1>C1(C)C=CC=CC=1.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:19][C:20]2[CH:41]=[CH:40][CH:39]=[C:22]([O:23][C:24]3[CH:38]=[CH:37][C:27]4[N:28]=[C:29]([NH:31][C:32]([CH:34]5[CH2:35][CH2:36]5)=[O:33])[S:30][C:26]=4[CH:25]=3)[CH:21]=2)=[O:11])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)sc5c4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
To a suspension of 3-(1-cyanocyclopropyl)benzoic acid (156.5 mg, 0.836 mmol) in toluene (5 mL) was added thionyl chloride (0.2 mL, 2.74 mmol) and the mixture was heated under reflux for 2 hr. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The obtained residue was used as 3-(1-cyanocyclopropyl)benzoyl chloride. 3-(1-Cyanocyclopropyl)benzoyl chloride prepared above was dissolved in pyridine (5 mL), N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (114.8 mg, 352.8 gmol) and N,N-dimethylpyridine-4-amine (23.9 mg, 195.6 μmol) were added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with dilute hydrochloric acid (50 ml), and extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (50 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/98→80/20) to give the title compound (117 mg, 67%) as a pale-brown amorphous substance.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH:12]=[C:13]3[NH:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:17][C:13](=[CH:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][CH:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[C:14](=[O:19])[NH:15]1
Reactant: O=C1CCN(c2ccc(C=C3NC(=O)NC3=O)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4NC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-imidazolidine-2,4-dione (which was obtained in Example 42) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp>201° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.75–1.95 (m, 2 H), 2.50–2.90 (m, 5 H), 2.92 (s, 3 H), 3.70–3.85 (m, 2 H), 4.48 (dd, J=8.0, 4.2 Hz, 1 H), 6.33 (s, 1 H), 6.81 (d, J=8.1 Hz, 1 H), 6.95 (d, J=8.7 Hz, 2 H), 7.02 (dd, J=8.1, 1.8 Hz, 1 H), 7.18 (d, J=61.8 Hz, 1 H), 7.47 (d, J=8.7 Hz, 2 H); MS (ES) m/z: 516.1 (MH+); HRMS Calcd. for C24H30N5O6S (MH+): 516.1917. Found: 516.1922.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:5].C(N(CC)CC)C.[CH2:22]([O:29][CH2:30][C:31](Cl)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:14])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:31](=[O:32])[CH2:30][O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(N)cc1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc(NC(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To a mixture of 2-(4-aminophenoxy)-propionic acid methyl ester 10 (20 grams, 102.5 mmol) and triethylamine (23 ml, 165 mmol) in acetone (120 ml) at 0° C. was added dropwise benzyloxy acetyl chloride (28 g, 152 mmol) followed by stirring at room temp for 12 hours. The solids were filtered off, acetone distilled off, and water (100 ml) added. Crude 51 was extracted into chloroform, washed with 5% sodium bicarbonate (2×100 ml) and water (200 ml), then dried over sodium sulphate and distilled. Crude 51 was purified by column chromatography on silica gel using benzene as eluant to get pure 51 (21 g, 59.8%) as a light brown powder with an m.p. between 67-70° C.
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([CH2:9][OH:10])[CH:5]=1)([CH3:3])[CH3:2].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([O:10][CH2:9][C:6]2[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[O:8][N:7]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CC(C)c1cc(CO)no1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCc2cc(C(C)C)on2)cc1
Reaction time: 5 h
Yield: 20.5 %

Procedure:
4.24 g of (5-i-propyl-isoxazol-3-yl)methanol was dissolved in 10 ml of pyridine, and 6.67 g of 4-toluenesulfonyl chloride was then added under ice-cooling. The mixture was stirred for 5 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.82 g of (5-i-propyl-isoxazol-3-yl)methyl 4-toluenesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[CH:6]=O.[CH3:14][N:15]1[CH:19](P(OCC)(=O)OCC)[C:18](=[O:28])[NH:17][C:16]1=[O:29]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:5]([CH:6]=[C:19]2[N:15]([CH3:14])[C:16](=[O:29])[NH:17][C:18]2=[O:28])[CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Product: COc1ccc([N+](=O)[O-])c(C=C2C(=O)NC(=O)N2C)c1
Yield: 93 %

Procedure:
Reaction of 3-methoxy-6-nitrobenzaldehyde with diethyl 1-methyl-2,4-dioxoimidazolidine-5-phosphonate according to the procedure of Method D provided the title compound as a mixture of geometrical isomers, m.p. 257°-260° C. in 93% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:24][C:23]([C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=2)=[O:25])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Product: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccc([N+](=O)[O-])cc1

Procedure:
The procedure described in Example 8 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.65 g of 4'-nitroacetophenone. Yield 1.25 g (38%), m.p. 255°-256° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:13][CH3:14])=[N:5][C:6]([OH:12])=[C:7]([CH:11]=1)C(O)=O)#[N:2].C1CCCCC1>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:12][C:6]1[CH:7]=[CH:11][C:3]([C:1]#[N:2])=[C:4]([S:13][CH3:14])[N:5]=1
Reactant: CSc1nc(O)c(C(=O)O)cc1C#N
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: C1CCCCC1
Product: CSc1nc(O)ccc1C#N
Yield: 60.6 %

Procedure:
A solution of 6 g (28.5 mmol) of 5-cyano-2-hydroxy-6-(methylthio)nicotinic acid in 35 ml of diphenyl ether is stirred at 250° C. for 4 hours. After returning to room temperature, 100 ml of cyclohexane is added and the reaction medium is triturated for 30 minutes. The solid formed is filtered, rinsed thoroughly with cyclohexane and then dried under vacuum to yield 2.87 g (60%) of 6-hydroxy-2-(methylthio)nicotinonitrile in the form of a brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[C:28]([O:30]CC)=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:15])=[O:16])[CH2:10][CH:9]1[C:28]([OH:30])=[O:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In tetrahydrofuran (40 ml), 1-tert-butoxycarbonyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonylpiperazine (23.0 g) was dissolved, followed by the addition of ethanol (40 ml) and a 3N aqueous sodium hydroxide solution (30 ml). The resulting mixture was stirred at room temperature for 3 hours. To the reaction mixture, 1N hydrochloric acid was added to make it acidic and then ethyl acetate was added to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate. The solid precipitated by distilling off the solvent under reduced pressure was collected by filtration, whereby the title compound (23.8 g, quant.) was obtained as a colorless solid.
Reaction SMILES: CC1C2N=C(N)SC=2C(Cl)=CC=1.[OH-].[Na+].[Na].[CH3:16][C:17]1[C:22]([NH:23][C:24](N)=[O:25])=[C:21]([SH:27])[C:20]([Cl:28])=[CH:19][CH:18]=1>>[Cl:28][C:20]1[C:21]2[S:27][C:24]([OH:25])=[N:23][C:22]=2[C:17]([CH3:16])=[CH:18][CH:19]=1
Reactant: Cc1ccc(Cl)c(S)c1NC(N)=O
Agent: Cc1ccc(Cl)c2sc(N)nc12
Agent: [Na+]
Agent: [Na]
Product: Cc1ccc(Cl)c2sc(O)nc12
Yield: 85.2 %

Procedure:
A mixture of 99.25 parts of 4-methyl-7-chloro-2-aminobenzothiazole, 20 parts of solid sodium hydroxide and the glycolic mother liquor mentioned in Example 8 is heated for 4 hours with agitation at 160°-165° C. The batch is then cooled with agitation to a temperature of 20°-30° C., and operations for cyclization of the precipitated sodium salt of 6-methyl-3-chloro-2-mercaptophenylurea are as indicated in Example 8. 85 Parts of 7-chloro-4-methyl-2-hydroxybenzothiazole having a melting point of 265.5°-266° C. are obtained, which corresponds to a yield of 85.2% of th.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:5]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4]1.CCN(C(C)C)C(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>CS(Cl)(=O)=O.CCOC(C)=O>[CH3:41][S:42]([O:1][CH2:2][C@@H:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:16]([F:17])([F:18])[F:19])[C:20]([F:21])([F:22])[F:23])=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:5]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4]1)(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](CO)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A 150-mL round-bottomed flask was charged with tert-butyl (3R)-3-(hydroxymethyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.393 g, 0.857 mmol), DIPEA (0.450 mL, 2.58 mmol) and EtOAc (5 mL). The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (0.095 mL, 1.2 mmol, Sigma-Aldrich, St. Louis, Mo.) was added dropwise. The mixture was stirred at 0° C. for 1 h. At that time, 4 drops of methanesulfonyl chloride was added and stirring at 0° C. resumed for 10 min. The material was directly purified by column chromatography (25 g of silica, 0 to 50% EtOAc in hexanes) to afford tert-butyl (3R)-3-(((methylsulfonyl)oxy)methyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.311 g) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([CH:16]=O)=[CH:4][CH:3]=1.C(O)C.C([O-])(=O)C.[Na+].Cl.[NH2:27][OH:28]>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([CH:16]=[N:27][OH:28])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C=NO
Reaction time: 0.08 h

Procedure:
15.45 g (60.2 mmol) of tert-butyl (6-chloro-3-formylpyridin-2-yl)carbamate (Example 106A) are introduced into 750 ml of ethanol, and a solution of 225 ml of water and 9.38 g (120.4 mmol) of sodium acetate is added and stirred for 5 min. A solution of 225 ml of water and 8.36 g (114.4 mmol) of hydroxylamine hydrochloride is added, and the mixture is stirred at RT for 4 h. The reaction mixture is concentrated in a rotary evaporator at 20° C. The residue is taken up in ethyl acetate and washed twice with saturated sodium hydroxide carbonate solution and once with saturated sodium chloride solution. The organic phase is separated off, dried over magnesium sulphate and concentrated in a rotary evaporator at 20° C. 15.5 g (80% of theory) of the product are obtained as a solid.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34].[O:36]=[C:37]1[C:46]2[NH:47][CH:48]=[C:49]([C:50](O)=[O:51])[C:45]=2[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[NH:38]1.[Cl-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:50]([C:49]1[C:45]2[C:44]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[NH:38][C:37](=[O:36])[C:46]=2[NH:47][CH:48]=1)=[O:51]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CN(C)CCNC(=O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
49 mg (0.36 mmol) of 1-hydroxybenzotriazole, 69 mg (0.36 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 73 μL (0.66 mmol) of N-methylmorpholine and 40 μL (0.36 mmol) of N,N-dimethylethylenediamine are added to 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) suspended in 0.7 ml of anhydrous dimethylformamide. The reaction mixture is stirred overnight at room temperature. The mixture is diluted with ethyl acetate (20 mL) and a saturated solution of sodium chloride (20 mL). The two phases are separated and the aqueous phase is extracted with ethyl acetate (3×20 mL). The organic phases are combined, washed with n aqueous solution of potassium carbonate (10%) (3×40 mL), water (40 mL) and a saturated solution of sodium chloride (50 mL), dried over magnesium sulfate and evaporated. The residue obtained is triturated in diethyl ether to give 13 mg (13%) of N-(2-dimethylamino-ethyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide in the form of a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37](=[O:43])[NH:38][CH:39]1[CH2:42][NH:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:43])[NH:38][CH:39]1[CH2:42][N:41]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:30])[F:29])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:40]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)NC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidin-3-yl)-carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and azetidin-3-yl-carbamic acid tert-butyl ester following General Procedure C.
Reaction SMILES: COC1C=CC(C2C=CC3C(=CC=C(OC)C=3)C=2)=C(N)C=1.BrC1C=CC(OCCN2CCCCC2)=C(F)C=1.[F:39][C:40]1[CH:41]=[C:42]([NH:55][C:56]2[CH:61]=[C:60]([O:62]C)[CH:59]=[CH:58][C:57]=2[C:64]2[CH:73]=[CH:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74]C)[CH:70]=3)[CH:65]=2)[CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>>[F:39][C:40]1[CH:41]=[C:42]([NH:55][C:56]2[CH:61]=[C:60]([OH:62])[CH:59]=[CH:58][C:57]=2[C:64]2[CH:65]=[C:66]3[C:71](=[CH:72][CH:73]=2)[CH:70]=[C:69]([OH:74])[CH:68]=[CH:67]3)[CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(Nc2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(N)c1
Agent: Fc1cc(Br)ccc1OCCN1CCCCC1
Product: Oc1ccc(-c2ccc3cc(O)ccc3c2)c(Nc2ccc(OCCN3CCCCC3)c(F)c2)c1
Yield: 71.8 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxynaphthalen-2-yl)phenylamine and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, [3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl][5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]amine (425 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (288 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1.C(N(C(C)C)C(C)C)C.C(Cl)Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)=[O:13])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Nc1ccc(F)cc1
Reactant: Nc1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(O)cc1)c1ccccc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100-mL RBF was combined 2-(4-fluorophenylamino)benzoic acid (2.5 g, 11 mmol), HATU (4.9 g, 13 mmol), 4-aminophenol (1.0 g, 9.2 mmol), N-ethyl-N-isopropylpropan-2-amine (3.2 mL, 18 mmol), and DCM (23 mL, 9.2 mmol). The reaction mixture was allowed to stir at RT overnight and was then absorbed onto a loading cartridge and passed through an 80 g silica gel column using hexanes: EtOAc as eluent. Fractions containing pure product were concentrated in vacuo to afford 2-(4-fluorophenylamino)-N-(4-hydroxyphenyl)benzamide as a brown oil. The oil was triturated with CH2Cl2 and hexanes, and the resulting solid was filtered through a 0.45 μM membrane filter and rinsed with hexanes. 2-(4-fluorophenylamino)-N-(4-hydroxyphenyl)benzamide was isolated as a off-white solid. Calcd for C19H15FN2O2: [M]+=322. Found: [M+H]+=323.