Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]([C:7]1([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)[CH2:5][CH3:6].[CH2:20]([O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34](F)=[C:35]([Cl:38])[CH:36]=2)[CH:31]=[CH:30][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O>[CH2:20]([O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:13][CH:10]3[CH2:11][CH2:12][C:7]([CH:4]([NH2:3])[CH2:5][CH3:6])([CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:8][CH2:9]3)=[C:35]([Cl:38])[CH:36]=2)[CH:31]=[CH:30][N:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCC(N)C1(C2CCOCC2)CCC(O)CC1
Reactant: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(N)C1(C2CCOCC2)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Yield: 23.5 %

Procedure:
To a suspension of sodium hydride (60%, 167 mg, 4.17 mmol, 3 eq.) in dimethyl acetamide (8 mL) was added a solution of 4-(1-aminopropyl)-4-(tetrahydropyran-4-yl)-cyclohexanol (7,369 mg, 1.53 mmol, 1.1 eq.) in dimethyl acetamide (8 mL). After stirring for 60 min at room temperature a solution of 1-benzyloxy-7-chloro-6-fluoro-isoquinoline (1,400 mg, 1.39 mmol) in dimethyl acetamide (8 mL) was added and stirring was continued first at room temperature, then at 50° C. until the reaction went to completion. The reaction was quenched by addition of water (30 mL) and the reaction mixture was extracted three times with a mixture of dichloromethane and 2-propanol (3:1). The combined organic layers were evaporated, and the obtained crude product was purified by flash chromatography (SiO2, 0%→30% methanol in dichloromethane) to yield 83 mg (earlier eluting isomer 1, 8) and 48 mg (later eluting isomer 2, 9) of the pure diastereoisomers as racemates respectively. The relative stereochemistry was not assigned. Additionally, 166 mg of the product as a diastereomeric mixture could be isolated. Rt=0.92 min (8), 0.93 min (9) (Method B). Detected mass: 419.4 (M+H+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:32])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: [OH-]
Reactant: COc1cccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)c1
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c1

Procedure:
In analogy with Example 44d), 1.315 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(3-methoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 49.9 ml of dimethoxyethane and 25.16 ml of water are hydrolysed with 12.36 ml of a 1M lithium hydroxide solution to give the title compound, which is directly subjected to further processing. TLC Rf (C)=0.09. FAB-MS (M+H)+ =444.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(P(CCCC)CCCC)CCC.[Cl:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]([C@@H:41]([CH2:51][CH2:52]O)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:43])[CH2:36][CH2:35][CH2:34]2>C1COCC1>[Cl:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]([C@H:41]1[CH2:51][CH2:52][N:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:42]1=[O:43])[CH2:36][CH2:35][CH2:34]2
Reactant: O=C(Nc1ccccc1)[C@H](CCO)N1CCCc2cc(Cl)ccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C1[C@@H](N2CCCc3cc(Cl)ccc32)CCN1c1ccccc1
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
Prepared using general procedure 61: To a yellow solution of di-tert-butyl azo-dicarboxylate (2.23 g, 9.7 mmol) in THF (25 mL) at 0° C. under N2 was slowly added tributylphosphine (2.4 mL, 9.7 mmol), The resulting colorless solution of the Mitsunobu reagent was stirred at RT for 10 min, and then added to a solution of (S)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxy-N-phenylbutanamide (2.56 g, 7.4 mmol) in THF (25 mL) at 0° C. under N2. The reaction mixture was stirred for 10 min. at this temperature, and quenched by addition of a saturated aqueous NaHCO3 solution. EtOAc was added, the phases were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4 and concentrated. Purification via silica gel chromatography using 20-40 EtOAc in hexane gave (S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-1-phenylpyrrolidin-2-one as a white solid (2.43 g, 100%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=327.5; tR=1.50 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1Br.[OH-].[Na+].[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17](B(O)O)[CH:18]=1>COCCOC.O.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:15]1[CH:14]=[C:13]([F:12])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Clc1cccc(Cl)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(F)cc1-c1c(Cl)cccc1Cl
Temperature: 90 °C
Yield: 61.6 %

Procedure:
To a solution of 2,6-dichlorobromobenzene (3.5 g, 15.7 mmol) and sodium hydroxide (3.14 g, 78.5 mmol) in DME-water (2:1) was added 5-fluoro-2-methoxybenzene boronic acid (4.0 g, 23.5 mmol) at 90° C., followed by tetrakis(triphenylphosphine)palladium (0) (0.9 g, 0.78 mmol). The reaction mixture was heated at 90° C. overnight and cooled to room temperature. The mixture was extracted with methylene chloride and washed with water. The organic solvent was removed under vacuum. Chromatography with 5% ethyl acetate in hexanes afforded 2.62 g (87%) of 2′,6′-dichloro-5-fluoro-2-methoxybiphenyl as a colorless oil. MS (EI) m/z 270 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[C:10]([N:15]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16]3)=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)=[C:29]=[O:30]>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[C:10]([N:15]3[CH2:19][CH2:18][CH:17]([NH:20][C:29]([NH:28][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=4)=[O:30])[CH2:16]3)=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:3][CH:2]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: NC1CCN(c2nccnc2OCc2ccncc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)NC1CCN(c2nccnc2OCc2ccncc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
To a solution of 1-[3-(pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-ylamine (50 mg, 0.18 mmole), triethylamine (excess eq.) in dichloromethane was added 1-isocyanato-3-trifluoromethyl-benzene (37 mg, 0.198 mmole). The mixture was stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo, and purified by preparative HPLC to give N-(1-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}pyrrolidin-3-yl)-N′-[3-(trifluoro-methyl)phenyl]urea (13.2 mg, 12.5% yield). 1H NMR (DMSO-d6) 8.80 (m, 3H), 7.97 (s, 1H), 7.90 (d, 2H), 7.68 (d, 1H), 7.4 (m, 2H), 7.3 (d, 1H), 7.2 (m, 1H), 6.8 (d, 1H), 5.3 (s, 2H), 4.25 (m, H), 3.9 (m, 1H), 3.75 (m, 2H), 3.6 (m, 1H), 2.40 (m, 1H), 1.85 (m, 1H) ppm.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[N:32]1([CH2:38][CH2:39][OH:40])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:35]3[CH2:36][CH2:37][N:32]([CH2:38][CH2:39][OH:40])[CH2:33][CH2:34]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: OCCN1CCNCC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN(CCO)CC3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using product of Example 75 step i) and 2-piperazin-1-yl-ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].CCN(CC)CC.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([S:11]([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=2[Cl:1])[C:6]([OH:8])=[O:7])(=[O:13])=[O:12])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc(C(=O)O)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 4-chloro-3-(chlorosulfonyl)benzoic acid (200 mg, 0.784 mmol) and Et3N (130 μl, 0.938 mmol) in CH2Cl2 (5 ml) was added 1-(t-butoxycarbonyl)piperazine (161 mg, 0.864 mmol) at 0° C. This mixture was stirred at room temperature overnight, and then diluted with CH2Cl2, washed with 10% citric acid solution. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was suspended in Et2O, and the precipitate was collected by filtration to give crude 3-{[4-(tert-butoxycarbonyl)-1-piperazinyl]sulfonyl}-4-chlorobenzoic acid (200 mg, 63.0%).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C:9](=[O:24])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([CH:21]=O)[C:15]=2[F:23])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[BH4-].[Na+]>CCO>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C:9](=[O:24])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([CH2:21][NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:15]=2[F:23])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(C=O)c1F
Reactant: Nc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(CNc2ccccc2)c1F
Temperature: 0 °C
Yield: 76.9 %

Procedure:
To a solution of (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-formyl-phenyl)-2-ethoxy-acetamide (250 mg, example 311.3) in EtOH (5 ml) was added aniline (64 mg). The suspension was stirred over night, then cooled to 0° C. and treated with NaBH4 (38 mg). The reaction mixture was stirred 1 h at 0° and 1 h at rt, then poured onto ice and extracted with EtOAc. The organic layer was dried over MgSO4, filtrated and concentrated. The crude product was purified by flash chromatography (cyclohexane/EtOAc 1:4=>EtOAc) to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-phenylaminomethyl-phenyl)-2-ethoxy-acetamide (230 mg) as off-white amourphous solid. MS 436.3 ([M+H]+)
Reaction SMILES: C(OC(=O)[N:7]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([Br:26])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:33]1[C:32]2[CH:37]=[CH:38][C:29]([CH2:28][NH:7][CH:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[C:21]([Br:26])[CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][C:17]4=[O:27])[CH2:10][CH2:9]3)=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(Br)cccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=c1ccc2c(Br)cccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2 mL of a chloroform solution containing 244 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-bromo-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform], to give 143 mg of (1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-bromoquinolin-2(1H)-one as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].ClC(Cl)(Cl)C[O:14][C:15](=[O:36])[CH:16]([S:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=1>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][CH2:27][S:26][CH:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][O:9][C:8](=[O:10])[CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:22][CH:23]=2)[C:15]([OH:36])=[O:14])=[CH:30][CH:31]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Reactant: O=C(O)Cc1ccccn1
Product: O=C(Cc1ccccn1)OCc1ccc(CC(SCCc2ccc(F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared starting from 2-pyridineacetic acid (HCl salt) and 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2-trichloro-ethyl ester in the same manner as described for example 7 (yield: 8.6 mg, 29%). 1H-NMR (300 MHz, CDCl3): δ 2.83-3.16 (m, 6H), 3.54-3.71 (m, 1H), 3.64 (s, 2H), 5.06-5.20 (m, 2H), 6.91-7.00 (m, 2H), 7.09-7.35 (m, 7H), 7.66 (brd, 1H), 8.06 (brs, 1H), 8.45 (brd, 1H); Mass Spectrum: M+H+ 455.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)=[O:16].CO.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)=[O:16]
Reactant: COC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(N)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 13 h
Yield: 97 %

Procedure:
3-Amino-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.01 g) is suspended in tetrahydrofuran (20 ml)-methanol, thereto is added 4 N aqueous sodium hydroxide solution (5 ml) under ice-cooling and the reaction solution is stirred at room temperature for 13 hours. The reaction solution is concentrated under reduced pressure, the resulting residue is diluted with water, and the mixture is adjusted to around pH 3 by pouring 10% hydrochloric acid. The precipitates are collected by filtration, washed with water and ethanol successively and dried to give the title compound (1.87 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[Cl:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH2:30](O)[CH2:31][OH:32]>C1C=CC=CC=1>[Cl:12][C:3]1[CH:4]=[C:5]([C:9]2([CH3:10])[O:32][CH2:31][CH2:30][O:11]2)[CH:6]=[C:7]([Cl:8])[C:2]=1[NH2:1]
Reactant: OCCO
Reactant: CC(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: CC1(c2cc(Cl)c(N)c(Cl)c2)OCCO1

Procedure:
1-(4-Amino-3,5-dichlorophenyl)ethanone (15 g, 73.5 mmol), pyridinium p-toluene sulfonic acid (5.5 g, 22 mmol), and ethylene glycol (6.2 mL, 110 mmol) were heated together in benzene (250 mL) with a Dean Stark trap at 100° C. overnight. The benzene was distilled off until ˜75 mL remained and the reaction mixture was extracted with EtOAc and saturated NaHCO3. The organic layer was separated, dried with MgSO4, filtered, and concentrated under rotary evaporation to afford a oily residue. The crude mixture was purified on silica gel chromatography (100% Hex to 100% EtOAc) to afford the desired product.
Reaction SMILES: [P:1](=[O:9])([N:6]=[C:7]=[O:8])([S:4][CH3:5])[O:2][CH3:3].[NH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1>CCOCC>[CH3:3][O:2][P:1]([NH:6][C:7]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1)=[O:8])([S:4][CH3:5])=[O:9]
Reactant: COC(=O)C1CCCNC1
Reactant: COP(=O)(N=C=O)SC
Solvent: CCOCC
Product: COC(=O)C1CCCN(C(=O)NP(=O)(OC)SC)C1
Temperature: 25 °C

Procedure:
A solution of 8.36 g of O,S-dimethyl phosphoroisocyanatidothioate in 100 ml of ether was cooled to 0° C. and to it was added dropwise with stirring 7.15 g of methyl 3-piperidinecarboxylate. The mixture was allowed to warm to ambient temperature and react overnight. The precipitate that formed was collected by filtration, extracted with ether, and dried under reduced pressure to obtain 11.5 g (74 percent of theory) of the title compound as white crystals melting at 65°-67° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)=[O:5])[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H](c2ccc([N+](=O)[O-])cc2)CC(=O)N1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1[C@@H](c2ccc(N)cc2)CC(=O)N1C
Reaction time: 18 h
Yield: 92.4 %

Procedure:
A solution of (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-nitrophenyl)pyrrolidin-2-one (2.00 g, 6.85 mmol) in EtOAc (15 mL) was added to an argon flushed flask containing 10% palladium on carbon (160 mg). The resulting mixture was placed under an atmosphere of H2 and stirred for 18 h. The reaction mixture then was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-aminophenyl)pyrrolidin-2-one (1.66 g, 92%) as a pale oil: TLC (EtOAc) Rf0.48; HPLC ES-MS m/z (rel abundance) 263 (MH+, 100%).
Reaction SMILES: [OH:1][C:2]([CH3:31])([CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[NH:15][CH:16]=[C:17]([S:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)=[O:13])=[CH:7][C:6]=1[O:28][CH3:29].Br[CH2:33][CH2:34]Br.[OH-].[Na+]>ClC(Cl)C.CCOC(C)=O>[OH:1][C:2]([CH3:31])([CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:34][CH2:33][N:15]3[CH:16]=[C:17]([S:19][CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[C:14]3[C:12]2=[O:13])=[CH:7][C:6]=1[O:28][CH3:29]
Reactant: COc1cc(NC(=O)c2cc(SCCc3ccccc3)c[nH]2)ccc1OCC(C)(C)O
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COc1cc(N2CCn3cc(SCCc4ccccc4)cc3C2=O)ccc1OCC(C)(C)O
Temperature: 50 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
A mixture of N-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(phenethylthio)-1H-pyrrole-2-carboxamide (20.0 mg, 0.0450 mmol), 1,2-dibromoethane (20.0 μL, 0.227 mmol), NBu4Br (43.5 mg, 0.135 mmol) and 1N NaOH (0.227 mL, 0.227 mmol) in dichloroethane (0.227 mL) was allowed to stir at 50° C. for 4 h. The reaction mixture was cooled to rt, diluted with EtOAc (20 mL), washed with water (×2, 15 mL), brine, dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC: PHENOMENEX® Luna AXIA 5μ C18 21.2×100 mm, 15 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 5 min hold; 20 mL/min, UV detection at 220 nm, 8.949 min retention time to afford 11.5 mg of the title compound as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 6 H), 2.86-2.91 (m, 2 H), 2.92-2.98 (m, 2 H), 3.83 (s, 2 H), 3.85 (s, 3 H), 4.05-4.11 (m, 2 H), 4.24-4.28 (m, 2 H), 6.78-6.84 (m, 2 H), 6.93 (d, J=8.2 Hz, 1 H), 6.96 (d, J=2.2 Hz, 1 H), 7.07 (s, 1 H), 7.18 (d, 7=8.2 Hz, 2 H), 7.21 (d, 7.1 Hz, 1 H), 7.26-7.32 (m, 2 H); HPLC a) column: PHENOMENEX® Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 3.470 min retention time, (>95%); HPLC b) column: PHENOMENEX® Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 3.461 min retention time; MS (ESI) 467 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:9]([O:16]C)=[N:10][C:11]([O:14]C)=[N:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O1CCOCC1.[ClH:24]>>[ClH:24].[F:1][C:2]1[C:7]([C:8]2[C:9](=[O:16])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1ncc(-c2cccnc2F)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]cc(-c2cccnc2F)c(=O)[nH]1

Procedure:
A solution of 5-(2-fluoro-3-pyridinyl)-2,4-bis(methyloxy)pyrimidine (Prep87, 2.8 g, 11.90 mmol) in HCl 4M in 1,4dioxane (42 mL, 168 mmol) was heated at 90° C. for 1 h. A white precipitate crashed out of the solution. Volatiles were evaporated under reduced pressure to give title compound, pale yellow solid (2.75 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH:18]=O)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1.N1CCCCC1>CO>[C:1]([O:5][C:6](=[O:20])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1/[CH:18]=[C:26]1\[C:27](=[O:31])[NH:28][C:29]2[C:25]\1=[CH:24][CH:23]=[C:22]([Cl:21])[CH:30]=2)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 83.8 %

Procedure:
To a mixture of 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (5.17 g, 17.3 mmol) and 6-chlorooxindole (2.89 g, 17.3 mmol) were anhydrous methanol (100 mL) at room temperature was slowly added piperidine (1.7 mL, 17.3 mmol). The reaction mixture was heated at 70° C. for 0.5 h. Then the mixture was cooled to room temperature and filtered. The precipitate was dried and collected to give E/Z-2-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid tert-butyl ester as a yellow solid (Yield 6.5 g, 84%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3]([CH:1]=[O:2])=[N:4][NH:5]3)=[CH:10][CH:9]=2)=[O:14])=[CH:17][CH:18]=1
Reactant: O=Cc1n[nH]c2cc(C(=O)O)ccc12
Reactant: Nc1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1n[nH]c2cc(C(=O)Nc3ccc(O)cc3)ccc12
Reaction time: 2 h

Procedure:
To a solution of 3-formyl-1H-indazole-6-carboxylic acid (1.6 g, 8.4 mmol) and 4-aminophenol (1.8 g, 16.8 mmol) in dry dimethylformamide (35 mL) was added HATU (3.8 g, 16.8 mmol) followed by triethylamine (1.4 mL, 10.1 mmol). The reaction was stirred at room and monitored by TLC and LC/MS. After two hours the reaction was complete. The solvent was removed by vacuum and the product was purified by flash column chromatography using ethyl acetate: petroleum ether 1:1 to pure ethyl acetate. N-(4-Hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide was isolated as a tan colored solid. 1H NMR (DMSO-d6) δ 6.79 (2H, d, 8.9 Hz), 7.59 (2H, d, 8.9 Hz), 7.94 (1H, d, 9.8 Hz), 8.24 (1H, d, 8.2 Hz), 8.31 (1H, s), 9.31 (1H, br s), 10.27 (2H, s). MS (APCI pos) 282.1.