Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([C:29]6([C:32]([O:34]C)=[O:33])[CH2:31][CH2:30]6)[CH:26]=[CH:27][CH:28]=5)[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.O[Li].O.Cl>CC(C)=O>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([C:29]6([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]6)[CH:26]=[CH:27][CH:28]=5)[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: COC(=O)C1(c2cccc(-c3nc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)ccc3C)c2)CC1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C2(C(=O)O)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 1-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-3-methylpyridin-2-yl)phenyl)cyclopropanecarboxylate (−0.26 mmol) was dissolved in acetone (3 mL) and water (3 mL) in a reaction tube. LiOH.H2O (25 mg, 60 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was acidified with 1N HCl until pH 1-2. The volatiles were removed under reduced pressure. The residue was taken up in methylene chloride and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The solid was triturated with Et2O, then hexanes to 1-(3-(6-(1-(2,2-difluorobenzo [d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-3-methylpyridin-2-yl phenyl)cyclopropanecarboxylic acid. ESI-MS m/z 493.2 (M+1)+. Retention time 1.80 minutes.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C>ClC(Cl)C>[C:1]([NH:8][C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)c1ccsc1N
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCCCC(=O)Nc1sccc1C(=O)OC
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Valeryl chloride (1.3 g) was added to a solution of methyl 2-aminothiophene-3-carboxylate (1.6 g) [Y. Kuwada et al. Chem. Abst. 82, 156252(1975)] and triethylamine (1.2 g) in dichloroethane (20 ml) under ice-cooling. The mixture was stirred for two hours. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as a colorless oil (2.3 g, 96%).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[NH:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:7]1([CH2:6][CH2:5][O:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[N:17]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: Brc1ccccc1OCCN1CCOCC1
Reactant: C1CNCCNC1
Product: c1ccc(N2CCCNCC2)c(OCCN2CCOCC2)c1

Procedure:
The title compound was prepared in a manner similar to Preparation 63A except that 4-[2-(2-bromo-phenoxy)-ethyl]morpholine was coupled to homopiperazine.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[N:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:14][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH:2]([F:12])[F:1])[N:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cccc(OC(F)F)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)Oc1cccc(CBr)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (6-(difluoromethoxy)pyridin-2-yl)methanol (250 mg; 1.42 mmol) in anh. DCM (12 ml) was treated at rt with CBr4 (473 mg; 1.42 mmol), and with PPh3 (374 mg; 1.42 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 1 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 2-(bromomethyl)-6-(difluoromethoxy)pyridine as a yellow oil which was directly used for the next reaction. LC-MS (conditions D): tR=0.95 min.; [M+H]+: 237.82 g/mol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:13](=[O:18])N(OC)C)[C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[Li][CH3:21]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:13](=[O:18])[CH3:21])[C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
[1(S)-(Methoxy-methyl-carbamoyl)-2,2-dimethylpropyl]-carbamic acid-tert-butyl ester (2.0 g, 7.3 mmol) was dissolved in, freshly distilled THF under an argon atmosphere. The solution was cooled to −78° C. whereupon MeLi (15.6 mL, 1.4 M in diethyl ether, 21.9 mmol, 3 eqv) was added dropwise maintaining an internal temperature <−70° C. The reaction was stirred at −70° C. for 30 minutes before warming to −30° C. for a further 30 minutes. After this time TLC analysis indicated the complete consumption of starting material. Saturated aqueous ammonium chloride solution (10 mL) was added and the reaction allowed to warm to room temperature. The aqueous phase was extracted with ethyl acetate (3×30 mL). The organic phases were washed with water (3×50 mL) and brine (50 mL), dried over MgSO4, filtered and the solvents removed in vacuo to give a crude yellow oil. Purification by column chromatography (SiO2, 20% ethyl acetate in hexanes) afforded the title compound as a colourless oil (1.355 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[Br-:11].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(=O)([O-])[O-].[Ca+2]>C(Cl)Cl.CO>[NH2:10][C:9]1[CH:8]=[C:7]([Br:11])[S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: [Br-]
Reactant: COC(=O)c1sccc1N
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1sc(Br)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Methyl-3-amino-2-thiophene carboxylate (1 eq. 25 g) was dissolved in 250 ml methylene chloride and 250 ml of methanol. Phenyl trimethylammonium tribromide (3 eq. 180 g) was added followed by calcium carbonate (4 eq. 63.75 g) and the reaction was left stirring at room temperature overnight. The calcium carbonate was filtered off and the filtrate concentrated down and water (750 ml) was added followed by ethyl acetate (1 L). The ethyl acetate layer was washed with more water, sodium thiosulfate, saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography to yield 21.46 g (57%) of methyl 3-amino-5-bromothiophene-2-carboxylate as a light brown oil, MH+=238.1.
Reaction SMILES: [C:1](#[N:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1([O:26]P(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1>[Rh]>[CH:20]([CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]#[N:19])=[O:26]
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: CCCCCCCC/C=C\CCCCCCCC#N
Agent: [Rh]
Product: CCCCCCCCCCCCCCCCC(C#N)C=O
Temperature: 130 °C

Procedure:
Into a 1 liter, 316 SS autoclave equipped with stirrer and heat exchange coil is placed 617 grams of olenitrile, 3.0 grams of 5 percent rhodium on aluminum (Englehardt Industries) and 3.2 grams of triphenylphosphite. The autoclave is flushed with nitrogen then pressurized with carbon monoxidehydrogen (1:1) to 1080 psig. The temperature is increased to 127-133 degrees C. and maintained from 3.3 hours with a CO--H2 pressure of 970-1080 psig. At this point a GC analysis indicated complete reaction of oleonitrile with the formation of FON. The reaction was cooled, the pressure vented and the product filtered. The yield of FON is 681. Rhodium is removed from the product by vacuum distillation.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=1)#[CH:9]>>[F:17][C:12]1[CH:11]=[C:10]([C:8]#[C:9][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: C#Cc1ccc(F)c(F)c1
Reactant: Ic1cccnc1
Product: Fc1ccc(C#Cc2cccnc2)cc1F
Yield: 21 %

Procedure:
Prepare essentially as described in EXAMPLE 46 using 3-iodopyridine (445 mg, 2.17 mmol) and 4-ethynyl-1,2-difluorobenzene, (prepared essentially as described in PREPARATION 14), (300 mg, 2.17 mmol) to give the title compound (87.6 mg, 21%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][C:25]([CH3:27])=C)[C:21]([O:28][CH2:29][O:30][CH3:31])=[C:20]([C:32]([O:34][CH2:35][O:36][CH2:37]OC)=[O:33])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[O:40]=[O+][O-].CSC>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][C:25](=[O:40])[CH3:27])[C:21]([O:28][CH2:29][O:30][CH3:31])=[C:20]([C:32]([O:34][CH2:35][O:36][CH3:37])=[O:33])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: C=C(C)Cc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)OCOCOC)c1OCOC
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cc(CC(C)=O)c(OCOC)c(C(=O)OCOC)c3)cs2)cc1OCC
Reaction time: 1 h

Procedure:
In 20 ml of methanol was dissolved 1 g of 2-(3,4-diethoxyphenyl)-4-[3-methoxymethoxymethoxycarbonyl-4-methoxymethoxy-5-(2-methyl-2-propenyl)phenyl]thiazole. Into the solution being stirred under ice-cooling was blown ozone. After 1 hour, 0.5 ml of methyl sulfide was added. The mixture was stirred at the same temperature for 30 minutes. The solvent was removed from the reaction mixture by distillation. To the residue were added 50 ml of dichloromethane and 25 ml of water. The organic layer was separated, washed with 15 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane/n-hexane=2/3 by v/v) to obtain 500 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-acetylmethylphenyl)thiazole as a colorless oily substance.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:20]1([CH2:26][CH2:27]Cl)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][CH2:27][O:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][C:8](=[O:18])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: O=c1oc2ccccc2c(OCCN2CCCCC2)c1-c1ccccc1
Yield: 73 %

Procedure:
10 g. (0.042 mol) of 3-phenyl-4-hydroxy-coumarin and 10.1 g. (0.55 mol) of 2-piperidino-1-chlorethane hydrochloride are caused to react in the manner described in Example 1. 10.8 g. of a yellow oil are obtained, which cannot be crystallised. Yield 73% (theoretical yield 14.7 g.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[CH:15][N:16]=[C:10]3[CH:9]=2)[CH2:3][CH2:2]1.Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[C:21]([O:28][C@@H:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:36])[CH2:31][C@H:30]3[F:45])[CH:22]=[CH:23][CH:24]=2)[N:19]=1>>[F:45][C@H:30]1[C@H:29]([O:28][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[N:19]=[C:18]([C:14]2[N:11]4[CH:12]=[CH:13][C:8]([O:7][CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:9][C:10]4=[N:16][CH:15]=2)[CH:27]=[CH:26]3)[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:31]1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3ccc(Cl)nc23)[C@H](F)C1
Reactant: c1cn2ccc(OC3CCOCC3)cc2n1
Product: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3ccc(-c4cnc5cc(OC6CCOCC6)ccn45)nc23)[C@H](F)C1

Procedure:
Prepared according to the procedure used for Example 1, Step D, using 7-(tetrahydro-2H-pyran-4-yloxy)imidazo[1,2-a]pyridine in place of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine and (trans)-benzyl 4-(2-chloroquinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate in place of 2,8-dibromoquinoline. MS APCI (+) m/z 597 (M+1) detected.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34].CN(C=O)C>[Cu](I)I.O>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][CH2:26][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=2[C:13]2[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1=2
Reactant: Clc1ccccc1CCBr
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2Cl)CCN(C)CC1
Temperature: 90 °C
Reaction time: 12 h
Yield: 14.2 %

Procedure:
The title compound was prepared by following general procedure 4. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1.0 mmol) was taken with copper iodide (19 mg, 0.1 mmol), L-praline (23 mg, 0.2 mmol), potassium phosphate tribasic (426 mg, 2.0 mmol), 1-(2-bromoethyl)-2-chlorobenzene (219 mg, 1.0 mmol) and DMF was added, the reaction was stirred at 90° C. under argon atmosphere for 12 h and monitored by LCMS. After completion of the reaction water was added and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase chromatography to afford 50 mg of the title compound (10.7%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([NH2:23])=[O:22])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[I:24]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([NH2:23])=[O:22])[C:9]=2[I:24])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccnc(N)n2)cc1C(N)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccnc(N)n2)c(I)c1C(N)=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 42.9 %

Procedure:
5-(2-Amino-pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide (1.1 g, 3.36 mmol) in dry DMF (6 mL) was treated with solid N-iodosuccinimide (830 mg, 3.69 mmol), stirred at room temperature for 4.5 h and poured into iced water (150 mL). The solid was then filtered with suction, washed thoroughly with water, dried in an oven under vacuum at 50° C. and purified by flash chromatography over silica gel (DCM/MeOH/7 N NH3 in MeOH 95/5/0.5) to afford the title compound (654 mg, 43%).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:25]([O-])([O-:27])=[O:26].[NH4+]>C(Cl)Cl>[N+:25]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][C:1]2=[O:11])=[CH:6][CH:7]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1CCCc2ccccc21
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 41.2 %

Procedure:
14.62 g of 1-tetralone in 45 ml of methylene chloride were treated with 29.3 ml of trifluoroacetic anhydride and 8.40 g of ammonium nitrate while cooling with ice/NaCl. After 18 hours the mixture was poured cautiously into an ice/conc. NaOH solution and extracted with diethyl ether. The organic phase was washed in succession with soda solution and NaCl solution, dried and evaporated. Flash chromatography on silica gel (hexane/ethyl acetate=9/2) followed by recrystallization from hexane/ethyl acetate (1/1) yielded 7.87 g of 7-nitro-1-tetralone as brownish crystals of m.p. 104°-105° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].S(=O)(=O)(O)O.O.[CH2:12](O)[CH2:13][CH2:14][CH3:15]>>[C:1]([O:5][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCCCO
Reactant: C=CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: C=CC(=O)OCCCC

Procedure:
A cascade of stirred vessels, consisting of three stirred reactors each having a reaction volume of one liter and equipped with column, condenser and phase separation vessel, was charged with 500 g of the crude acrylic acid discharged from the quench, 570 g of butanol and 13 g of sulfuric acid per hour. The reaction temperature in the reactors was 106° C., 118° C. and 123° C.; the pressure was 700 mbar in each case. At the top of the column a mixture of water, butanol and butyl acrylate was obtained which separated into an aqueous and an organic phase. 300 ppm of phenothiazine were added to the organic phase, which was then passed as a reflux to the column.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:16](=[O:34])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>O.C(O)C>[C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:16](=[O:34])[C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:33])[C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[CH:21][CH:22]=2)[CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2CC(C(=O)O)Cc3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To 3-ethoxycarbonyl-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.6 g) are added an aqueous solution of sodium hydroxide (0.1 g) in water (1 ml) and ethanol (5 ml). The mixture is stirred at room temperature for 15 minutes, and acidified with diluted hydrochloric acid, extracted with dichloromethane. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane→dichloromethane:methanol=50:1), and recrystallized from ethanol to give 3-carboxy-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.4 g) as white powder, m.p. 221°-223° C.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][N:41]=2)[CH:36]=[CH:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[N:34]1([CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=2)[C:42]2=[N:41][CH:40]=[CH:39][CH:38]=[C:37]2[CH:36]=[CH:35]1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: c1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cn2ccc3cccnc32)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
To a 50-mL round-bottomed flask was added ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (50 mg, 0.095 mmol, Intermediate B), 7-azaindole (16.76 mg, 0.142 mmol, Alfa Aesar, Ward Hill, Mass.) and cesium carbonate (62 mg, 0.19 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at 80° C. for 18 h. The mixture was allowed to cool to room temperature. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. Purification by silica gel chromatography, eluting with 50% EtOAc in hexanes gave 2-(4-((S)-2-((1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (28 mg) as a mixture of two isomers.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:4][C:5](=O)[C:6]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][S:9][C:7]=2[N:8]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:5]1[C:6]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][S:9][C:7]=2[N:8]=[C:3]([CH2:2][Cl:1])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(CCl)nc2scc(-c3ccccc3)c12
Product: ClCc1nc(Cl)c2c(-c3ccccc3)csc2n1
Temperature: 105 °C

Procedure:
A suspension of 2-(chloromethyl)-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one (1.50 g, ex Enamine) in phosphorus oxychloride (23 mL) was heated to reflux (105° C.) overnight. The reaction was cooled and the solvent was evaporated. Toluene (30 mL) was added and the mixture was evaporated again. The residue was dissolved in dichloromethane (100 mL). It was washed with water (1×100 mL) and saturated aqueous sodium bicarbonate solution (1×100 mL), dried (sodium sulfate), filtered and evaporated to give the target compound as a yellow solid (1.45 g). m/z [M+H]+ 294.8/296.8. Retention time 4.99 min (LCMS method+ve 6 min). It was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([CH3:26])[CH2:22][C:23]([OH:25])=[O:24])=[N:19][CH:20]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].S(=O)(=O)(O)O.[CH3:32]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([CH3:26])[CH2:22][C:23]([O:25][CH3:32])=[O:24])=[N:19][CH:20]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(CC(=O)O)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(O)c2)cn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(O)c2)cn1

Procedure:
(RS) 3-{5-[2-(3-hydroxy-4-nitrophenyl)-acetylamino]-pyridin-2-yl}-butanoic acid (2.1 g, Reference Example 26) in methanol (80 mL) was treated with concentrated sulphuric acid (0.5 mL). The mixture was heated at reflux temperature for 24 hours, then cooled, then concentrated to low volume and then diluted with ethyl acetate. This solution was washed with 5% aqueous sodium bicarbonate, then with water, then dried over magnesium sulphate and then evaporated to give the title compound (2.0 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:9]([CH:10]2[CH2:12][CH2:11]2)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:13][CH2:14][CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[N:3]=1.[B:20]1([OH:30])[C:24]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=2[CH2:22][O:21]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[CH:10]1([C:9]2[C:2]([O:29][C:27]3[CH:26]=[CH:25][C:24]4[B:20]([OH:30])[O:21][CH2:22][C:23]=4[CH:28]=3)=[N:3][C:4]([O:13][CH2:14][CH2:15][O:16][CH:17]([CH3:19])[CH3:18])=[C:5]([CH:8]=2)[C:6]#[N:7])[CH2:12][CH2:11]1
Reactant: CC(C)OCCOc1nc(Cl)c(C2CC2)cc1C#N
Reactant: OB1OCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)OCCOc1nc(Oc2ccc3c(c2)COB3O)c(C2CC2)cc1C#N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-5-cyclopropyl-2-(2-isopropoxyethoxy)nicotinonitrile (150 mg, 0.53 mmol), benzo[c][1,2]oxaborole-1,5(3H)-diol (84 mg, 0.56 mmol) and Cs2CO3 (209 mg, 0.64 mmol) in DMSO (20 mL) was stirred at 40° C. overnight. The mixture was diluted by water, extracted by EtOAc, the separated organic layer was concentrated in vacuo and the residue was purified by column chromatography (Petroleum ether:EtOAc=10:1˜1:1) to afford 5-cyclopropyl-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-(2-isopropoxyethoxy)nicotinonitrile. (120 mg, 57%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 9.18 (s, 1H), 7.86 (s, 1H), 7.76 (d, J=8.0, 1H), 7.24 (d, J=2.0, 1H), 7.16 (dd, J=8.0, 2.0, 1H), 4.96 (s, 2H), 4.04 (m, 2H), 3.42 (m, 2H), 2.05 (m, 2H), 0.97 (d, J=6.0, 6H), 0.92 (m, 2H), 0.77 (m, 2H).