Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:22][C:21]=1[O:35]CC1C=CC=CC=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].CCO>[Pd].C1COCC1.CCO>[C:1]([O:5][C:6](=[O:43])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:22][C:21]=1[OH:35])(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)CCCN(C)C)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)CCCN(C)C)cc1O
Reaction time: 19.5 h
Yield: 83 %

Procedure:
(S)-3-[2-Benzyloxy-4-(4-dimethylamino-butanoylamino)-benzenesulfonylamino]-4,4-diethoxy-butyric acid tert-butyl ester (0.62 g, 1.0 mmol) was shaken with 20% palladium on carbon (0.06 g) in THF-EtOH (1:1) under H2 (50 psi) for 16 h using a Parr apparatus. Mass spectrometry and NMR analysis indicated only starting material to be present. An additional 0.28 g of 20% Pd/C and EtOH (50 mL) were added and allowed to stir for 19.5 h. TLC analysis showed complete consumption of starting material. The reaction mixture was filtered through celite and concentrated to yield (S)-3-[4-(4-dimethylamino-butanoylamino)-2-hydroxy-benzensulfonylamino]-4,4-diethoxy-butyric acid tert-butyl ester (0.44 g, 0.83 mmol, 83%). MS (APCI) m/z 532.4 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:32][N:33]([CH:35]=O)[CH3:34].[CH3:37][N:38]1C=CC=C1[Sn](CCCC)(CCCC)CCCC>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>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:32]1[N:33]([CH3:34])[CH:35]=[CH:37][N:38]=1)=[N:3][CH:4]=[CH:5]2)(=[O:13])=[O:14]
Reactant: CN(C)C=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4nccn4C)nccc3c2)c(OC)c1
Temperature: 90 °C

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate OOO; 0.050 g, 0.105 mmol), Pd(Ph3P)4 (0.012 g, 10.50 μmol), and DMF (0.525 ml). 1-Methyl-2-(tributylstannyl)-1H-pyrrole (0.078 ml, 0.210 mmol) was added and the reaction was heated in a microwave reactor at 90° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 100% EtOAc:Heptane with a 10% MeOH/DCM flush) to afford N-(2,4-dimethoxybenzyl)-1-(1-methyl-1H-imidazol-2-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as an off-white solid. m/z (ESI) 522.2 (M+H)+. The material was dissolved in DCM and TFA (8.09 μl, 0.105 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, triturated with diethyl ether, and filtered. The solids were washed with diethyl ether and the filtrate was concentrated and purified via column chromatography (12 g silica gel column, gradient elution 0 to 10% MeOH:EtOAc) to afford 1-(1-methyl-1H-pyrrol-2-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.93 (br. s., 1H), 9.12 (s, 1H), 8.81 (d, J=5.7 Hz, 1H), 8.64 (s, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 8.10 (s, 1H), 8.00 (dd, J=1.9, 8.9 Hz, 1H), 7.30 (d, J=4.5 Hz, 1H), 6.89 (d, J=4.5 Hz, 1H), 3.88 (s, 3H). m/z (ESI) 371.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)O)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)C(O)=O>CCOC(C)=O>[CH2:37]([N:3]([CH2:1][CH3:2])[C:4](=[O:36])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[C:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)=[CH:9][CH:10]=1)[CH3:38]
Reactant: CCN(CC)C(=O)c1ccc(C(O)(c2cccc3cccnc23)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2cccc3cccnc23)cc1
Yield: 83.5 %

Procedure:
A mixture of the compound of Example 19 (45 mg), trifluoroacetic acid (1.0 mL) and trifluoromethanesulforic acid (1 mL) was refluxed for 8 hrs., and then condensed. The residue was dissolved in AcOEt (50 ml). The resulting solution was washed with 1 N NaOH solution, aqueous NH4Cl solution and brine, dried over Na2SO4. Removal of solvents gave a crude product, which was purified by silica gel column eluting with NH4OH (1N)-MeOH—CH2Cl2 (2.5:17.5:80) to provide N,N-diethyl-4-(8-quinolinyl-piperidin-4-ylidene-methyl)-benzamide (29 mg, 84%):
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].CO[C:13](OC)([N:15]([CH3:17])[CH3:16])[CH3:14]>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[C:13]([N:15]([CH3:17])[CH3:16])[CH3:14])=[CH:5][CH:6]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1ccc(Cl)cc1
Product: CC(=CC(=O)c1ccc(Cl)cc1)N(C)C

Procedure:
A mixture of 25.0 g of 4-chloroacetophenone and 40 ml of N,N-dimethylacetamide dimethyl acetal was stirred and heated at reflux for 3 hours. The mixture was evaporated in vacuo to give a red solid. The solid was triturated with n-hexane and filtered. The solid was washed with n-hexane and dried to give 15.6 g of 1-(4-chlorophenyl)-3-(dimethylamino)-2-buten-1-one as red crystals, mp 103°-105° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:25])[CH2:23][OH:24])=[CH:18][CH:17]=1.C(Cl)(Cl)Cl>CO>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:25][C@H:22]([C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1)[CH2:23][OH:24])[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](CO)c1ccccc1
Yield: 23 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with D-phenylglycinol to provide the title compound in 23% yield as yellow needles (flash chromatography on SiO2, eluent CHCl3, MeOH, AcOH—15, 1, 0.2).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:35]([CH3:34])(=[O:37])=[O:36])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(C)(=O)=O)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.85 mg, 0.25 mmol) in dichloromethane (6 ml) was added methylsulfonyl chloride (28.20 mg, 0.25 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 28 mg (47%); 1H NMR (DMSO-d6, 300 MHz): δ 9.214 (s, 1H), 7.953-7.984 (d, 1H, J=9.3 Hz), 7.85-7.88 (d, 2H, J=8.4 Hz), 7.72-7.76 (m, 3H), 6.771-6.778 (d, 1H, J=2.1 Hz), 3.3727 (s, 3H), 1.774 (s, 6H); MS: m/z 485 (M+).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][CH2:5][S:6][CH2:7][CH:8]([OH:12])[CH:9]([OH:11])[CH3:10].C[O-].[Na+].Cl>CO.O>[OH:12][CH:8]([CH:9]([OH:11])[CH3:10])[CH2:7][S:6][CH2:5][CH2:4][C:3]([OH:13])=[O:2]
Reactant: COC(=O)CCSCC(O)C(C)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)C(O)CSCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
6,7-dihydroxy-4-thiaoctanoic acid methyl ester as obtained in Reference Example 44 (1.47 g) was dissolved in a mixture of methanol (20 ml) and water (1 ml). To this solution, sodium methylate (1.5 ml) was added under ice cooling conditions, followed by stirring at room temperature for 1 day. To the reaction mixture, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate; the solvent was distilled off under reduced pressure to yield the title compound (1.00 g, yield 73%) as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[I-].[CH2:9]([NH:27][C:28]1[C:29]([NH2:34])=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C.O.C(OCC)(=O)C>[CH2:9]([N:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]=[C:2]1[C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)C=O
Reactant: CCCCCCCCCCCCCCCCCCNc1ccccc1N
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCn1c(C(=O)OCC)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
Ethyl glyoxylate (7.861 g) and iodide (4.886 g) were added to a solution containing N-octadecyl-1,2-benzenediamine (6.940 g) in ethanol (100 ml) and the mixture was stirred for 2 hours at room temperature. A solution containing sodium thiosulfate pentahydrate (4.813 g) in water (60 ml) was added dropwise to the reaction mixture while being stirred. The reaction mixture, with ethyl acetate added thereto, was washed with saturated brine, dried over sodium sulfate anhydride, and concentrated. The residue (10.06 g) was purified by silica gel column chromatography (silica gel 255 g, chloroform), thereby yielding the entitled compound (6.442 g) as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17]1([CH2:23][CH2:24][OH:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1.C1(C=C)C=CC=CC=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: OCCc1ccccc1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C=Cc1ccccc1
Product: N#Cc1c(OCCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, 2-phenylethanol and DBU in DME. EI-MS m/e (%): 316 (M+, 4), 212 ([M—PhCH═CH2]+, 100), 184 (28), 170 (20), 104 ([PhCH═CH2]+, 84), 77 (20).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[C:23]([CH3:28])[N:22]=1.N12CCCN=C1CCCCC2>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:20][C:21]1[N:26]=[C:25]([N:17]2[CH2:18][CH2:19][CH:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=4)[CH2:9][CH2:10]3)[CH2:15][CH2:16]2)[CH:24]=[C:23]([CH3:28])[N:22]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Cc1cnc(N2CCC(C3CCNCC3)CC2)cn1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnc(N2CCC(C3CCN(c4cc(C)nc(Cl)n4)CC3)CC2)cn1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
The 1-(5-methylpyrazin-2-yl)-4,4′-bipiperidine (720 mg, 2.8 mmol) and 2,4-dichloro-6-methyl-pyrimidine (502 mg, 3.1 mmol) were dissolved in NMP (30 mL), and the solution cooled to −20° C. The 1,8-diazabicyclo[5.4.0]-undec-7-ene (4.2 mL, 28 mmol) was added drop-wise and the solution stirred for 10 minutes. The mixture was diluted with ethyl acetate (50 mL), washed with brine (30 mL×2), dried over magnesium sulfate, filtered and concentrated in vac. The residue was purified by chromatography on silica gel with 30% acetone: hexanes to yield the title compound.
Reaction SMILES: C([O:5][C:6](=[O:44])[CH:7]([NH:12][C:13]([C:15]1[C:16]([S:21][S:22][C:23]2[C:28]([C:29](=[O:43])[NH:30][CH:31]([C:36]([O:38]C(C)(C)C)=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C1(OC)C=CC=CC=1>[C:36]([CH:31]([NH:30][C:29]([C:28]1[C:23]([S:22][S:21][C:16]2[C:15]([C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([OH:44])=[O:5])=[O:14])=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:43])[CH2:32][CH:33]([CH3:35])[CH3:34])([OH:38])=[O:37]
Reactant: CC(C)CC(NC(=O)c1cccnc1SSc1ncccc1C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)CC(NC(=O)c1cccnc1SSc1ncccc1C(=O)NC(CC(C)C)C(=O)O)C(=O)O
Yield: 77.4 %

Procedure:
The general method of Preparation 20 was followed using [S-(R*,R*)]-2-([2-[3-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-pyridin-2-yldisulfanyl]-pyridine-3-carbonyl]-amino)-4-methyl-pentanoic acid tert-butyl ester (1.9 g, 2.9 mmol) in 20 mL dichloromethane, anisole (1.5 mL), and 10 mL trifluoroacetic acid. The crude product was recrystallized from methanol/water to yield 1.2 g of the title compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([OH:18])=O)=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:4])=[O:3].C1C=C2N=NN(O)C2=CC=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.[NH2:55][C@H:56]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C@@H:57]([OH:59])[CH3:58]>C(Cl)Cl>[OH:59][C@@H:57]([CH3:58])[C@H:56]([NH:55][C:16]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]=1[NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[O:18])[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: C[C@H](O)[C@H](N)c1ccccc1
Reactant: CS(=O)(=O)Nc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: C[C@H](O)[C@H](NC(=O)c1c(NS(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
A solution of 3-methanesulfonylamino-2-phenyl-4-carboxylic acid (1c) (250 mg, 0.73 mmol), HOBt hydrate (148 mg, 1.1 mmol), 4-methylmorpholine (160 μL, 1.46 mmol) in methylene chloride (15 mL) was added EDCI (210 mg, 1.1 mmol) at RT under N2. A mixture of (1R,2S)-1-amino-1-phenylpropan-2-ol hydrochloride and 4-methylmorpholine (193 μL, 1.75 mmol), in methylene chloride (5 mL) was added and the reaction mixture was stirred at RT for 16 h. Solution is partitioned against water and twice extracted with methylene chloride. The combined organic extracts are washed with brine, dried over magnesium sulfate and then concentrated in vacuo with added silica. The compound is subsequently eluted off the silica and chromatographed, eluting with 15-30% ethyl acetate/dichloromethane to give the title compound (167 mg, 48%). 1H NMR (500.333 MHz, CDCl3) δ 1.10 (d, J=6.6 Hz, 3H), 2.23 (s, 3H), 2.69 (d′, J=6.7 Hz, 1H), 4.44-4.47 (m, 1H), 5.35 (dd, J=8.4, 3.3 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.39 (dd, J=6.9, 6.9 Hz, 2H), 7.44 (d, J=7.5 Hz, 2H), 7.47-7.55 (m, 4H), 7.71-7.78 (m, 4H), 8.16 (d, J=8.4 Hz, 1H) MS APCI, m/z=476.1 (M+1). LCMS: 1.86 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][O:29][C:30]2[CH:31]=[C:32]([NH2:35])[NH:33][N:34]=2)[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([CH2:28][O:29][C:30]2[CH:31]=[C:32]([NH:35][C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([CH:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:17][CH:16]=3)[NH:33][N:34]=2)[CH:21]=[C:20]([O:19][CH3:18])[CH:25]=1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1ccc(C2CCN(C)CC2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(C4CCN(C)CC4)cc3)[nH]n2)cc(OC)c1
Yield: 46.7 %

Procedure:
N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(1-methylpiperidin-4-yl)benzamide was prepared following the procedure as for Example 159, but starting from methyl 4-(1-methylpiperidin-4-yl)benzoate (0.25 g, 1.07 mmol), 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.267 g, 1.07 mmol) and 2M trimethylaluminium in toluene (2.14 ml, 4.29 mmol). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 8% 2.5M NH3/MeOH in DCM. Pure fractions were evaporated to dryness, redissolved in DCM, triturated with ether and evaporated to dryness to afford the title compound (0.225 g, 46.5%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ 1.69 (1H, d), 1.73 (2H, d), 1.77 (1H, s), 1.95-2.02 (2H, m), 2.21 (3H, s), 2.88 (2H, d), 3.76 (6H, s), 5.09 (2H, s), 5.62 (1H, s), 6.45 (1H, s), 6.60 (2H, s), 7.41-7.42 (2H, m), 7.89-7.91 (2H, m), 10.85 (1H, s), 11.58 (1H, s). MS: m/z 451 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7].P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[O:5][C:6]([CH3:7])=[C:2]([CH2:1][Cl:18])[N:3]=2)=[CH:9][CH:10]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCl
Temperature: 25 °C

Procedure:
A solution of 4,5-dimethyl-2-(4-bromophenyl)-oxazole oxide (96.6 g, 0.36 mol) in CHCl3 (0.90 L) was treated dropwise with phosphorous oxychloride (61.1 g, 0.40 mol) allowing the reaction to exotherm and then was stirred at reflux for 30 min. The reaction was then cooled to room temperature and washed with water (2×1 L). The combined aqueous washes were back extracted with CH2Cl2 (2×400 mL). The organic layers were dried (MgSO4), and the solvent removed in vacuo to give crude product that was recrystallized from hot hexanes (300 mL), decanting the hot supernate away from a dark oily material. The remaining dark oil was agitated in additional hot hexanes (200 mL) and the combined supernates were cooled to 0° C. to crystallize the product which was isolated by filtration to give 74.2 g (72%) of 2-(4-bromophenyl-4-(chloromethyl)-5-methyloxazole as a lime-green powder: Rf=0.39 in 20% ethyl acetate/hexanes; 1H NMR (500 MHz, CDCl3) 7.88-7.86 (m, 2H), 7.59-7.56 (m, 2H), 4.54 (s, 2H), 2.42 (s, 3H); 13C (125 MHz, CDCl3) 159.2, 146.9, 133.2, 132.0, 127.6, 126.1, 124.7,37.1, 11.5; IR (KBr) 2970, 1633, 1599, 1481, 1401, 1258, 1117, 1008 cm−1; UV (EtOH)max281 nm (21349); HRMS (FAB) m/z calculated for C11H1079BrClNO: 285,9634, found 285.9641; Anal. Calculated for C11H9ClBrNO: C, 46.11; H, 3.17; N, 4.89; Cl, 12.37; Br, 27.88. Found C, 46.28; H 3.07; N, 4.81; Cl, 12.36; Br, 27.88.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])[CH2:2][CH3:3].[CH3:12][C:13]([CH3:15])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]2[O:8][C:13]([CH3:15])([CH3:12])[O:11][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: CC(C)=O
Reactant: CCCc1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCc1ccc2c(c1)OC(C)(C)O2

Procedure:
The same procedures as described in Example 10 were carried out by using a mixture of 7.61 g (50 mM) of 4-n-propylcatechol, 15 ml of acetone, 30 mg of p-toluenesulfonic acid monohydrate and 15 ml of benzene. 5-n-Propyl-2,2-dimethyl-1,3-benzodioxol was obtained in the yield of 9.13 g (47 mM) as colorless transparent liquid having a boiling point of 82°-87° C./3 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([BH3-])#N.[Na+]>C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: CCOC(=O)c1cc(Cl)cc2cc[nH]c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Cl)cc2c1NCC2
Product: Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 91 %

Procedure:
To a mixture of ethyl 5-chloro-1H-indole-7-carboxylate (3.0 g) and acetic acid (30 mL) was added sodium cyanoborohydride (2.5 g), followed by stirring at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, and the residue was adjusted to pH 8 by adding saturated aqueous sodium bicarbonate. After extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was added with diethyl ether/hexane (1/5), solidified, and collected by filtration. To this solid was added ethyl acetate (10 mL), and 4 M hydrogen chloride ethyl acetate (10 mL) was added thereto, followed by concentration under reduced pressure. To the residue was added diethyl ether/hexane mixture (1/5), and the solid was collected by filtration and dried under reduced pressure to obtain ethyl 5-chloroindoline-7-carboxylate hydrochloride (1.6 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CC#N>[CH3:13][S:14]([CH:4]([OH:5])[CH2:3][CH2:2][Cl:1])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)C(O)CCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of 3-chloro-1-propanol (283 g, 2.99 mol) and triethylamine (629 mL, 4.5 mol) in CH3CN (3500 mL) at 10 ° C. was added dropwise methanesulfonyl chloride (518 g, 4.52 mol). The resulting reaction mixture was stirred overnight at room temperature, filtered and concentrated in vacuo to an oil. The oil was dissolved in CH2Cl2 and purified by filtration through silica gel. The appropriate fractions were combined and concentrated in vacuo to give the title compound 335 g (65%). TLC (Rf: 0.3; 20% EtOAc/Hexane). 1H NMR (CDCl3) δ2.1 (m, 2H, CH2), 2.96 (s, 3H, CH3), 3.59 (t, 2H, CH2), 4.28 (t, 2H, CH2). 13C NMR (CDCl3) δ31.5 (CH2), 37.0 (CH3), 40.2 (CH2), 66.3 (CH2).