Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1

Procedure:
1-Butyl-4-[4-(4--chlorophenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (3.3 g, 6.9 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.08 g (67%); white solid; mp 201° C.; MS: 451.9 (M+H)+
Reaction SMILES: Cl[C:2]1[C:3](Cl)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH2:10]([OH:15])[CH2:11][CH:12]([CH3:14])[CH3:13]>>[CH3:13][CH:12]([CH3:14])[CH2:11][CH2:10][O:15][C:5]1[N:4]=[C:3]([O:15][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:2]=[C:7]([O:15][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[N:6]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)CCO
Product: CC(C)CCOc1cc(OCCC(C)C)nc(OCCC(C)C)n1
Temperature: 50 °C
Yield: 98.7 %

Procedure:
49.5 g (0.45 mol) of sodium t-amylate are dissolved in 200 ml of isopentanol at 50° C., and 13 ml (0.11 mol) of trichloropyrimidine in 50 ml of isopentanol are added dropwise to this solution over the course of 30 minutes. After the mixture has been warmed at 50° C. for one hour, thin-layer chromatography shows that the mixture no longer contains any starting material. The solvent is removed on a rotary evaporator, and the residue is poured into 200 ml of water. The mixture is extracted three times with 150 ml of toluene in each case, and the organic phases are dried using MgSO4 and filtered. Removal of the solvent gives 37.5 g (98.7% of theory) of 2,4,6-tris(3-methylbut-1-oxy)pyrimidine.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([N:6]([Si](C)(C)C)[Si](C)(C)C)=[CH:4][CH:3]=1.CON(C)[C:20](=[O:33])[CH2:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>O1CCCC1.O>[NH2:6][C:5]1[CH:15]=[CH:16][C:2]([C:20](=[O:33])[CH2:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[CH:3][CH:4]=1
Reactant: CON(C)C(=O)CCCN(C)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCCC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
4-Bromo-N,N-bis(trimethylsilyl)aniline (1.64 mL, 5.82 mmol) was dissolved in tetrahydrofuran (9 mL), and a 1.6 N n-butyllithium-hexane solution (3.23 mL, 5.33 mmol) was added at −78° C. A solution of tert-butyl {4-[methoxy(methyl)amino]-4-oxobutyl}methylcarbamate (1.26 g, 4.85 mmol) in tetrahydrofuran (9 mL) was further added at −78° C. The temperature was increased to room temperature, water (2 mL) was added, then 1 N tetrabutylammonium fluoride (10 mL, 10 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogencarbonate solution was added, then the mixture was extracted with dichloromethane and ethyl acetate, and the organic layers were combined and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvents, hexane:ethyl acetate=4:1→2:1, v/v) to give the title compound (1.32 g; yield, 71%).
Reaction SMILES: C(O)C.C([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22]([CH2:31][CH3:32])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[O:23]2)=[CH:18][CH:17]=1)C1C=CC=CC=1>[Pd].O>[OH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22]([CH2:31][CH3:32])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[O:23]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1(CC)CCc2ccc(OCCCOCc3ccccc3)cc2O1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(CC)CCc2ccc(OCCCO)cc2O1
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To an 80 ml ethanol solution of ethyl 7-(3-benzyloxypropoxy)-2-ethylchromane-2-carboxylate (3.76 g, 9.5 mmol) was added water 4 ml and 10% Pd/C 300 mg. This solution was placed in a Parr shaker and was shaken under hydrogen atmosphere (50 psi) overnight. The catalyst was removed by filtration through a pad of celite. The filtrate was concentrated and chromatographed on silica gel. Elution with 30% AcOEt/hexanes gave the title compound 2.88 g as colorless syrup (quant.).
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].S(=O)(=O)(O)O.C1(S(O)=O)C=CC=CC=1.[N:25]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])=[N:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28]>O>[C:1]1([S:7]([N:25]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[NH:26][C:27]([O:29][CH:30]([CH3:31])[CH3:32])=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: O=S([O-])c1ccccc1
Agent: O=S(=O)(O)O
Agent: O=S(O)c1ccccc1
Agent: [Na+]
Solvent: O
Product: CC(C)OC(=O)NN(C(=O)OC(C)C)S(=O)(=O)c1ccccc1
Temperature: 60 °C

Procedure:
To one-half mole of sodium benzenesulfinate in water in a 2 liter beaker is introduced 49 g (0.5 mole) of concentrated sulfuric acid. To the resulting suspension of benzenesulfinic acid is then added 101 g (0.5 mole) of diisopropyl azodicarboxylate. The mixture is stirred and heated to 60° C. (30 minutes). The yellow color of the azo ester gradually disappears. The oily product is extracted with benzene and separated from the lower aqueous layer. Removal of the benzene by evaporation leaves a clear oil which crystallizes when introduced into an 80/20 hexane/benzene mixture. The filtered crystals are dried at 60° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]2[C:8]([C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:11]=1)=[CH:7][CH:6]=[CH:5]2>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[N:4]2[C:8]([C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:11]=1)=[CH:7][CH:6]=[CH:5]2)=[O:1]
Reactant: COC(=O)c1ccc(CO)n2cccc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)n2cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a solution of methyl 5-(hydroxymethyl)indolizine-8-carboxylate (13 g, 63.41 mmol) in DCM (300 mL) was added MnO2 (55 g, 0.634 mol) at 0° C. The reaction mixture was stirred at rt overnight. After the completion, the reaction was filtered and concentrated. The crude product was purified by column (PE:EtOAc=300:1) to give the desired product methyl 5-formylindolizine-8-carboxylate (5.8 g, yield 45%). 1H NMR (400 MHz, DMSO): δ 10.01 (s, 1H), 8.90-8.91 (m, 1H), 7.31-7.35 (d, 1H, J=7.6 Hz), 7.68-7.70 (d, 1H, J=1 Hz), 7.29-7.31 (m, 1H), 7.14-7.16 (m, 1H), 3.97 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:36])[CH2:33][C:34]#[CH:35]>C(NCC)C.C(Cl)Cl.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:35]#[C:34][CH2:33][CH2:32][OH:36])[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(I)c21
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(C#CCCO)c21
Reaction time: 18 h

Procedure:
A solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide (0.074 g), copper iodide (0.013 g), Pd(PPh3)2Cl2 (0.007 g) and 3-butyn-1-ol (0.02 mL) in 7 mL diethylamine is stirred at room temperature for 3 days. The reaction is partitioned between CH2Cl2 and H20. The aqueous is extracted 3× with CH2Cl2. The organics are combined, dried over Na2SO4, filtered and concentrated. The residue is dissolved in CH2Cl2 and adsorbed onto silica. Purification by Biotage Flash 40S chromatography (eluent CH2Cl2 (1L), 0.5% MeOH/CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 1.5% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3% MeOH/CH2Cl2 (1L), 5% MeOH/CH2Cl2 (1L), 7% MeOH/CH2Cl2 (1L)) affords the product as a tan residue. The residue is dissolved in a minimal amount of CH2Cl2 and hexanes are added to affect recrystallization. The solution is placed in the freezer for 18 h after which the product is collected and dried (0.037 g, 57%).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([O:14][C:15]1[CH:38]=[CH:37][C:18]2[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]=2[CH:16]=1)[CH:22]=[C:21]([C:27]1[N:28]([CH2:32][C:33]([F:36])([F:35])[F:34])[N:29]=[CH:30][N:31]=1)[N:20]=3)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[NH3:40]>CO>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][CH2:5][C@H:4]([O:14][C:15]1[CH:38]=[CH:37][C:18]2[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]=2[CH:16]=1)[CH:22]=[C:21]([C:27]1[N:28]([CH2:32][C:33]([F:34])([F:36])[F:35])[N:29]=[CH:30][N:31]=1)[N:20]=3)[C:3]([NH2:40])=[O:2])([CH3:11])([CH3:12])[CH3:13]
Reactant: COC(=O)[C@H](CO[Si](C)(C)C(C)(C)C)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Reactant: N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid methyl ester was dissolved in ammonia in methanol (7 N, 10 mL) and the reaction mixture stirred at RT for 48 hr. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, gradient 0-5% methanol in ethyl acetate) to give (S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionamide as a yellow oil (101 mg, 49% over 2 steps). LCMS: RT=3.78 min, [M+H]+=553
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([NH:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[S:13][CH:14]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2Cl)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(Cl)cc3Cl)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(2,4-dichloro-phenyl)-thiazol-2-ylamine hydrobromide with 0.32 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and extracted three times with 40 ml of ethyl acetate each time. The organic extracts were combined, dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.50 g of N-[4-(2,4-dichloro-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as colorless crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2([O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)[OH:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:34]1([C:37]2[CH:42]=[CH:41][C:40]([CH2:43]C(OCC)=O)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1>>[CH:34]1([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:2]3[CH:9]=[C:8]([C@:10]4([O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]4[OH:13])[OH:11])[CH:7]=[CH:6][C:3]=3[C:4]#[N:5])=[CH:39][CH:38]=2)[CH2:36][CH2:35]1
Reactant: CC(=O)OC[C@H]1OC(O)(c2ccc(C#N)c(F)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(=O)Cc1ccc(C2CC2)cc1
Product: N#Cc1ccc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(C2CC2)cc1

Procedure:
Compound (27) may also be obtained by reacting 2-Fluoro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile (Compound XI(1)) and Ethyl 4-cyclopropyl-phenylacetate (Compound XXIV) under basic conditions followed by ester hydrolysis and decarboxylation.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]CC)=[O:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: CCOC(=O)CCCN
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)NCCCC(=O)O)cc2)cc1

Procedure:
The product from Example 100 and ethyl 4-aminobutyrate hydrochloride were processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 7.80 (br.s, 1 H), 7.13-7.33 (m, 8 H), 7.01 (m, 4 H), 6.88 (m, 4 H), 3.94-4.16 (m, 4 H), 3.06 (m, 4 H), 2.91 (s, 3 H), 2.39 (s, 2 H), 2.20 (m, 2 H), 2.07 (m, 2 H), 1.79 (m, 2 H), 1.61 (m, 2 H); MS (APCI) m/z 644 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[N:16]([O-])=O.[Na+]>CC(O)=O>[N+:13]([C:10]1[C:11]2[N:12]=[N:16][NH:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1)([O-:15])=[O:14]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(N)c(N)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc([N+](=O)[O-])c2nn[nH]c2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of methyl 3,4-diamino-5-nitrobenzoate (D245) (2.5 g, 12 mmol, 1 equiv) in AcOH (10 ml) at room temperature was added NaNO2 (900 mg, 13 mmol, 1.1 equiv) and the resulting mixture was stirred at 60° C. for 1 h, cooled to room temperature and concentrated in vacuo. the residue was partitioned between AcOEt and a 5% aqueous citric acid solution and the layers were separated. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. Trituration of the residue in Et2O/iso-hexane gave methyl 4-nitro-1H-1,2,3-benzotriazole-6-carboxylate (D246) (2.08 g, 78%) as an orange solid which was used in the next step without further purification. [M+H]+=223.3, RT=2.31 min.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].F[C:10]1[CH:15]=[CH:14][C:13]([S+:16]([C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[OH-].[Na+].[CH2:33]([SH:37])[CH2:34][CH2:35][CH3:36]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:33]([S:37][C:10]1[CH:15]=[CH:14][C:13]([S+:16]([C:24]2[CH:29]=[CH:28][C:27]([S:3][CH2:2][CH2:18][CH2:17][CH3:22])=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([S:16][CH2:13][CH2:12][CH2:11][CH3:10])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCS
Reactant: Fc1ccc([S+](c2ccc(F)cc2)c2ccc(F)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Br-]
Solvent: ClCCl
Product: CCCCSc1ccc([S+](c2ccc(SCCCC)cc2)c2ccc(SCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 120.8 %

Procedure:
26.7 g of tris(4-fluorophenyl)sulfonium trifluoromethanesulfonate was dissolved in 200 g of dichloromethane in a reaction flask, in which the atmosphere was replaced with nitrogen. 600 g of 10 wt % sodium hydroxide aqueous solution, 5.8 g of tetra-n-butylammonium bromide, and 20.1 g of n-butanethiol were added. The mixture was stirred for 30 minutes at room temperature and transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. After the addition of 300 ml of distilled water, the mixture was shaken and allowed to stand still. The water layer was removed. The dichloromethane solution was dried with anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dried solution, the residual liquid was dried under reduced pressure to obtain 23.4 g of tris(4-n-butylthiophenyl)sulfonium trifluoromethanesulfonate.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C@@H:11]([CH3:25])[CH2:10][C@H:9]2[N:26]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:27](=[O:30])[CH2:28][CH3:29].C([O-])([O-])=O.[K+].[K+]>CO.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([N:26]([C:27](=[O:30])[CH2:28][CH3:29])[C@H:9]2[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([CH:5]=[CH:4][C:3]([OH:38])=[O:2])[CH:7]=3)[N:12]([C:16](=[O:24])[C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C@@H:11]([CH3:25])[CH2:10]2)=[CH:32][CH:33]=1
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
To a solution of (±)-cis-3-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yl]-acrylic acid methyl ester (110 mg, 0.21 mmol) in 4 ml methanol was added 50 mg K2CO3, (0.36 mmol, in 2 ml water). The resulting reaction mixture was stirred at room temperature overnight. The methanol was removed under vacuum. 1M HCl was added until the mixture was acidic. Dichloromethane (25 ml) was added. Organic layer was dried with magnesium sulfate. Dichloromethane was removed under vacuum. The residue was purified by HPLC to give 10 mg title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:9])[C:5]([F:8])([F:7])[F:6])[CH3:2].[CH3:10][CH2:11][O:12][C:13](C(CBr)=O)=[O:14]>C1COCC1.O.C(Cl)Cl>[F:6][C:5]([F:8])([F:7])[C:4]1[S:9][CH:2]=[C:1]([C:13]([O:12][CH2:11][CH3:10])=[O:14])[N:3]=1
Reactant: CCNC(=S)C(F)(F)F
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1csc(C(F)(F)F)n1
Temperature: 95 °C
Yield: 42 %

Procedure:
To a stirring solution of ethyl 2,2,2-trifluoroethanethioamide (0.35 g, 2.71 mmol) in THF (12 ml) was added ethyl bromo pyruvate (0.375 ml, 2.98 mmol) at RT. Reaction mixture was heated at 90-100° C. for 16 h. Reaction mixture was diluted with water and DCM. The organic layer was separated and distilled out to get crude product which was column purified using 0-2% EtOAC in hexane to get titled compound in 42% yield.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(#N)C.[Si](Cl)(Cl)(Cl)Cl.C(Cl)Cl.[C:16]([C:18]1[C:19]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[Cl:39])=[C:20]([C:29]([NH2:31])=O)[S:21][C:22]=1[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)#[N:17]>>[Cl:39][C:33]1[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=1[C:19]1[C:18]([C:16]#[N:17])=[C:22]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:21][C:20]=1[C:29]1[NH:31][N:3]=[N:2][N:1]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1c(N2CCOCC2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1c(N2CCOCC2)sc(-c2nnn[nH]2)c1-c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
To a mixture of sodium azide (34.01 mg, 0.0005232 mol) in ACN (0.3 mL, 0.005 mol) was added silicon(IV) chloride (0.105 mmol, 0.000105 mol) in DCM (0.1 mL, 0.002 mol) and the mixture was stirred for 30 min. 4-cyano-3-(2,4-dichlorophenyl)-5-morpholinothiophene-2-carboxamide (20.0 mg, 0.0000523 mol) was added to the above mixture, followed by sodium azide (0.0340 g, 0.000523 mol) and silicon(IV) chloride (0.16 mmol, 0.00016 mol) in DCM (0.16 mL, 0.0025 mol) and the mixture was irradiated in microwave at 160° C. for 30 min. The reaction was evaporated and purified by column chromatography to afford 4-(2,4-dichlorophenyl)-2-morpholino-5-(1H-tetrazol-5-yl)thiophene-3-carbonitrile (11.6 mg, 54.4%). LCMS: (FA) ES+ 407.09, ES− 405.20; 1H NMR (300 MHz, d1-chloroform) δ: 7.60 (d, 1H), 7.42 (dd, 1H), 7.30 (d, 1H), 3.90-3.85 (m, 4H), 3.72-3.63 (m, 4H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:10]=1[NH:22][C:23]([C:25]1[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[N:27]([CH3:33])[CH:26]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[CH2:1]([N:8]1[C:9]2[CH:14]=[C:13]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH:12]=[CH:11][C:10]=2[N:22]=[C:23]1[C:25]1[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[N:27]([CH3:33])[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)Nc2ccc(N3CCN(C)CC3)cc2NCc2ccccc2)cn(C)c1=O
Solvent: CC(=O)O
Product: Cc1cc(-c2nc3ccc(N4CCN(C)CC4)cc3n2Cc2ccccc2)cn(C)c1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid [2-benzylamino-4-(4-methyl-piperazin-1-yl)-phenyl]-amide I-1′ (523.000 mg; 1.174 mmol) is dissolved in acetic acid and stirred at 80° C. overnight. The reaction mixture is concentrated under reduced pressure and the residue is purified on silica chromatography Combiflash (Column: Redisep Rf, 40 g; gradient: DCM/MeOH=100%/0% to 95%/5% over 30 column volumes, then to 90%/10% over 15 column volumes; flow rate=40 ml/min; detection wavelength: 254 nm). Product containing fractions are combined and concentrated under reduce pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[NH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH:26]([CH3:28])[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:26]([CH3:28])[CH3:27])[CH:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(c1ccnc(Cl)c1)c1c[nH]c2ccncc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)c2ccnc(Cl)c2)c2cnccc21
Reaction time: 18 h
Yield: 19.8 %

Procedure:
To a mixture of (2-chloropyridin-4-yl)-(1H-pyrrolo[3,2-c]pyridin-3-yl)methanone (Preparation 49, 34 g, 0.13 mol) in DMF (700 mL) was added Cs2CO3 (65 g, 0.2 mol) and 2-iodopropane (34 g, 0.2 mol) at room temperature and the reaction stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate from 10:1 to 1:1 to afford the title compound as a yellow solid (7.7 g, 23.6%).