Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O>CCCCCC>[Cl:17][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=c1[nH]cnc2ccc([N+](=O)[O-])cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
6-Nitro-3H-quinazolin-4-one 4a (18.88 g, 99.40 mmol) was dissolved in phosphoricchloride (31.03 g, 149 mmol). The mixture was warmed up to 160° C., and stirred for 3 hours. The reaction mixture was added to 250 mL of n-hexane while hot, stirred and a lot of the solid was precipitated from the solution, filtered, the filter cake was washed with n-hexane, dried under vacuum to obtain the title compound 4-chloro-6-nitro-quinazoline 4b (18.14 g, yield 87.2%) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[S:16][C:15]([C:18]([NH:20][C@@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)=[O:19])=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH:29]1([C:35]([Cl:37])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:37].[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([NH:20][C:18]([C:15]1[S:16][C:17]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:35]([CH:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:36])[CH:4]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=1)=[O:19])[CH2:22]2
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(NC(=O)C4CCCCC4)c3)c2s1

Procedure:
50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 35.4 mg (0.24 mmol) of cyclohexylcarbonyl chloride are reacted together by general method F. 9.8 mg (16.2% of theory) of the title compound are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>C(O)C.O1CCOCC1>[ClH:25].[ClH:25].[CH3:22][O:21][C:19]1[CH:18]=[C:17]([O:23][CH3:24])[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:20]=1
Reactant: COc1cc(OC)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc(OC)nc(NC2CCNCC2)n1

Procedure:
A solution of 4-(4,6-dimethoxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.97 g, 5.82 mmol) in ethanol (50 mL) and 4 M HCl in dioxane (75 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 239.1 [M+H]+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH:8]([NH:23][CH3:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N+:20]([O-])=O.O>[Fe].C(O)C>[NH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[CH2:9][CH:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[CH3:2])[NH:23][CH3:24]
Reactant: CNC(Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1sccc1C
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNC(Cc1ccc(C(F)(F)F)cc1N)c1sccc1C
Yield: 77.1 %

Procedure:
A mixture of 3.3 g of α-(3-methyl-2-thienyl)-N-methyl-2-nitro-4-trifluoromethylbenzeneethanamine hydrochloride, 4.8 g of iron powder, 13 ml of water, 50 ml of 95% ethanol, and concentrated 350 μl hydrochloric acid was refluxed for 1.5 hrs. The mixture was filtered through Celite, the filter cake washed with water, and the organic phase of the filtrate was concentrated in vacuo. The residue was diluted with 50 ml of water and basified with 10% (aq) sodium hydroxide solution. The aqueous phase was extracted with dichloromethane, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was triturated with hexane to afford 2.1 g of product, mp 52°-54° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:23]1[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=1)=[O:22].[Cl-].[NH4+]>O1CCCC1.C([Li])CCC>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:21]([C:23]2[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=2)[OH:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: CCOC(=O)c1ccc(C=O)o1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(O)c2cc3cc(SC)ccc3n2S(=O)(=O)c2ccccc2)o1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
To a solution of 1-benzenesulfonyl-5-methylthioindole (0.5178 g) in tetrahydrofuran (17 ml), n-butyl lithium (1.3 ml, 1.59 M) was added dropwise at −78° C. and the mixture was stirred for 30 minutes, followed by addition of the compound obtained in Example 30 (1) (0.3444 g), and the mixture was stirred at −50° C. for 40 minutes. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.593 g of the desired product.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:34]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[C:34]([C:42]5[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=5)[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: COc1ccc(-c2c(-c3ccccc3)c(Cl)nc3ccccc23)cc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3)c(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc3ccccc23)cc1
Yield: 42.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (60 mg, 0.23 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-3-phenyl-4-(4-methoxyphenyl)quinoline (95 mg, 0.27 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 56 mg (43%) of the title compound as an off white solid. mp 239°-242°. FDMS: m/e=570. α[D]589 =+45.00 (c=1.40, chloroform).
Reaction SMILES: CC(C)(OC(N1CC2C=C(C3C=CC=CC=3)C=CC=2NCC1)=O)C.[ClH:25].[NH:26]1[CH:30]=[C:29]([CH2:31][N:32]2[C:38]3[CH:39]=[CH:40][C:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:42][C:37]=3[CH2:36][N:35](C(C3C4C(=CC=CC=4)C=CC=3)=O)[CH2:34][CH2:33]2)[N:28]=[CH:27]1.Cl.Cl.N1C=C(CN2CC3C=CC=CC=3N(C(C3C4C(=CC=CC=4)C=CC=3)=O)CC2)N=C1.C(C1N=CNC=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].[OH-].[NH4+]>C(Cl)Cl.C(O)(=O)C>[ClH:25].[NH:26]1[CH:30]=[C:29]([CH2:31][N:32]2[C:38]3[CH:39]=[CH:40][C:41]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][C:37]=3[CH2:36][NH:35][CH2:34][CH2:33]2)[N:28]=[CH:27]1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccccc3)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCNc2ccc(-c3ccccc3)cc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(-c2ccc3c(c2)CNCCN3Cc2c[nH]cn2)cc1
Reaction time: 4 h

Procedure:
A solution of 2,3,4,5-tetrahydro-4-[(1,1-dimethylethoxy)-carbonyl]-7-phenyl-1H-1,4-benzodiazepine (prepared from Compound B of Example 12 as described for Compound A of Example 4, 0.20 g) and 4-formyl imidazole (0.52 g, 5.6 mmol) in CH2Cl2 (10 mL) and acetic acid (2 mL) was stirred for 40 min. Sodium triacetoxyborohydride (0.9 g, 6 mmol) was added and stirring was continued for 4 hrs. Sodium bicarbonate (sat., 5 mL) and ammonium hydroxide (conc, 5 mL) were added and the mixture was stirred for another 3 hrs. The aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with 1N NaOH (2×10 mL) and conc. NH4OH (10 mL), dried (Na2SO4) and evaporated. The residual solid was stirred in MeOH (5 mL) and aqueous HCl in dioxane (4 M, 10 mL) overnight. The solvent was evaporated and the residue was triturated with CHCl3 to give a solid (0.35 g) which was purified by preparative HPLC (methanol/water gradient with 0.1% TFA) and converted to the HCl salt by lyophilization from 1M HCl (5 mL) to provide Example 89 (0.12 g, 57%) as an off white solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[CH2:10]=[O:11]>>[CH2:1]([C:3]([CH2:10][OH:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2]
Reactant: C=O
Agent: CCCCC(C=O)CC
Product: CCCCC(C=O)(CC)CO

Procedure:
In U.S. Pat. No. 5,146,004, 2-ethyl-2-(hydroxymethyl) hexanal is prepared from 2-ethyl hexanal, formaldehyde and a tertiary amine. Any unreacted 2-ethyl hexanal can be isolated by azeotropic distillation of the organic phase of the raw product, and 2-butyl-2-ethyl-1,3 propane diol is obtained from the purified organic phase of the raw product by catalytic hydrogenation, with a yield of 85-88%. The hydrogenation is carried out by using a nickel catalyst.
Reaction SMILES: CS(O[CH2:6][CH:7]([CH3:28])[CH:8]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:9]1[C:17]2[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)(=O)=O.Br[C:30]1SC(C(C2C3C(=C(CSC)C=CC=3)NC=2)CCC#N)=C[N:34]=1>CS(C)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:7]([CH3:28])[CH2:6][C:30]#[N:34])=[CH:22][CH:23]=1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)C(C)COS(C)(=O)=O)c[nH]c12
Reactant: CSCc1cccc2c(C(CCC#N)c3cnc(Br)s3)c[nH]c12
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3)C(C)CC#N)c[nH]c12

Procedure:
The title compound was prepared starting from 215 mg (0.49 mmol) of the compound from Example 71A in analogy to the synthesis of the compound from Example 53, but with dimethyl sulfoxide as solvent. 177 mg (98% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[F:13][C:14]1[CH:15]=[C:16]([SH:20])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C.CCCCCCC>CN1C(=O)CCC1.O>[F:13][C:14]1[CH:15]=[C:16]([S:20][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCCc2cc(F)ccc21
Reactant: Fc1cccc(S)c1
Solvent: CN1CCCC1=O
Solvent: CCCCCCC
Solvent: O
Product: O=C1CCCc2cc(Sc3cccc(F)c3)ccc21
Temperature: 90 °C
Reaction time: 12 h
Yield: 92.8 %

Procedure:
A solution of 6-fluoro-3,4-dihydro-2H-naphthalen-1-one (3.64 kg) and 3-fluorothiophenol (2.80 kg), in anhydrous NMP (7.7 kg) was treated with triethylamine (2.26 kg). After a mild exotherm had subsided, the mixture was heated for 20 hours at 90° C. The mixture was cooled to about 25° C. and diluted with water (30 L) and heptane (10 kg). The mixture was agitated for 12 hours and then filtered. The filter cake was washed with water and dried at 60° C. under vacuum to afford 6-(3-fluorophenylsulfanyl)-3,4-dihydro-2H-naphthalen-1-one (5.52 kg): MP=66.2-66.7° C.; MS (M+1)=273; H1 NMR (300 MHz): δ ppm (CDCl3): 2.10 (2H, m, J=6.03, 6.40 Hz), 2.62 (2H, dd, J=6.03, 5.75 Hz) 2.87 (2H, t, J=6.03), 7.03 (1H, tdd, J=1.13, 2.64, 8.29 Hz), 7.08-7.16 (2H, m), 7.22 (1H, dt, J=1.13, 8.29 Hz), 7.31 (1H, q, 8.29 Hz), 7.35 (1H, dd, J=5.65, 7.91 Hz) 7.92 (1H, d, J=7.91 Hz).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH2:8][OH:9])[O:6][CH:7]=1.[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO.O>[OH:9][CH2:8][C:5]1[O:6][CH:7]=[C:2]([O:1][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3](=[O:10])[CH:4]=1
Reactant: O=c1cc(CO)occ1O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1cc(CO)occ1OCc1ccccc1

Procedure:
A suspension of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (56.8 g, 0.4 mole) in 400 ml of methanol was treated with sodium hydroxide, (16 g, 0.4 mole) in 200 ml of warm methanol followed by 50.6 g (46 ml, 0.4 mole) of benzyl chloride. The mixture was heated to reflux for 3.5 hours, cooled, and poured in 1 L of water. The resulting solid was filtered and washed with ca. 1.5 L of water, 200 ml of ethanol and 400 ml of hexane. After drying under high vacuum, the weight of product was 55.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=3)[CH2:11][C:10](=[O:24])[N:9]2[C:25]2[CH:26]=[CH:27][C:28]([N:31]([CH2:33][C@H:34]3[CH2:39][CH2:38][C@H:37]([NH:40][CH2:41][C:42]([NH:44][CH:45]([CH3:47])[CH3:46])=[O:43])[CH2:36][CH2:35]3)[CH3:32])=[N:29][CH:30]=2)=[CH:4][CH:3]=1.[CH2:48]=O>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH:19]([CH3:20])[CH3:21])[CH:16]=3)[CH2:11][C:10](=[O:24])[N:9]2[C:25]2[CH:30]=[N:29][C:28]([N:31]([CH2:33][C@H:34]3[CH2:35][CH2:36][C@H:37]([N:40]4[CH2:41][C:42](=[O:43])[N:44]([CH:45]([CH3:47])[CH3:46])[CH2:48]4)[CH2:38][CH2:39]3)[CH3:32])=[CH:27][CH:26]=2)=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(N(C)C[C@H]3CC[C@H](NCC(=O)NC(C)C)CC3)nc1)C(=O)C2
Solvent: CC(C)O
Product: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(N(C)C[C@H]3CC[C@H](N4CC(=O)N(C(C)C)C4)CC3)nc1)C(=O)C2

Procedure:
The mixture of Example 131 (80 mg, 0.121 mmol) and formaldehyde (0.090 mL, 37% solution, 10 eq., 1.208 mmol) was heated for 5 h in 2-propanol (4 mL) at 85° C. The mixture was concentrated to dryness and the residue was purified by reversed phase column chromatography. The fractions containing the product were pooled and worked up (addition of NaHCO3), yielding the title compound as an off-white solid (46 mg, 0.068 mmol, >98%). HPLC: HtRet=1.40 min; LC-MS: m/z 674.2 [M+H]+.
Reaction SMILES: N1C=CN=C1.[C:6]1([P:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.II.CC[O:29]CC>C(Cl)Cl>[C:19]1([P:12](=[O:29])([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOCC
Agent: II
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -2 °C
Reaction time: 0.25 h

Procedure:
A 12-L, three-neck, round-bottom flask equipped with a mechanical stirrer, thermocouple, nitrogen bubbler, and an additional funnel, was charged with imidazole (204 g, 2.99 mol, 6.0 equivalents), triphenylphosphine (300 g, 1.14 mol, 2.3 equivalents), and methylene chloride (2.5 L). The resulting solution was cooled to −2° C. and to this was added iodine (290 g, 1.14 mol, 2.3 equivalents). The resulting mixture was allowed to stir for 15 minutes, and then a solution of (12) (274 g, 0.50 mol) in methylene chloride (1.3 L) was added slowly, over 35 minutes. The resulting orange mixture was allowed to warm to room temperature where it was stirred for three hours. The reaction mixture was filtered, and the filtrate was washed successively with 2% aqueous sodium sulfite solution (1×2 L), 0.1 N aqueous hydrochloric acid solution (1×1.5 L), and saturated aqueous sodium chloride solution (1×1.5 L). The organics were then dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo to afford a yellow residue which was dissolved in ether (4 L) producing a white precipitate (triphenylphosphine oxide). The solution was filtered and the filtrate was evaporated in vacuo to afford 320 g of (13) as a yellow oil contaminated with triphenylphosphine oxide. This material was used in the next step without purification.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([S:21]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]3)(=[O:23])=[O:22])[C:16](=[O:34])[C:15]2([OH:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]>N1C=CC=CC=1>[C:5]1([O:4][C:2](=[O:3])[O:43][C:15]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[C:14]3[C:18](=[CH:19][CH:20]=[C:12]([Cl:11])[CH:13]=3)[N:17]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:33]=3[N:32]=[CH:31][CH:30]=[CH:29]4)(=[O:23])=[O:22])[C:16]2=[O:34])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1ccccc1C1(O)C(=O)N(S(=O)(=O)c2cccc3cccnc23)c2ccc(Cl)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: COc1ccccc1C1(OC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2cccc3cccnc23)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Phenyl chloroformate (0.35 ml, 2.79 mmol) was added dropwise to a solution of example 64 (300 mg, 0.624 mmol) in pyridine (6 ml) while cooling slightly. The reaction mixture was stirred at room temperature overnight. After addition of ice-water, the mixture was extracted with ethyl acetate, and the organic phase was washed several times with dilute citric acid solution and water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether, and the resulting precipitate was filtered off, washed with diethyl ether and dried. 310 mg of the desired intermediate were obtained.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O.[O:28]1[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29]1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.O.C(#N)C.CO>[O:28]1[CH:32]=[CH:31][C:30]([C:33]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)=[O:34])=[CH:29]1
Reactant: O=C1CCNCC1
Reactant: O=C(O)c1ccoc1
Agent: CCN=C=NCCCN(C)C
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CO
Product: O=C1CCN(C(=O)c2ccoc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-piperidone hydrochloride monohydrate (0.32 g, 2.1 mmol) was dissolved in DCM (7 ml), and to this was added MP-Carbonate resin (0.8 g). This was stirred at room temperature for 2 h. Separately, 3-furoic acid (0.28 g, 2.52 mmol), N N-4-dimethylaminopyridine (cat.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.3 mmol) and TEA (0.25 ml) were dissolved in DCM (7 ml) and stirred at room temperature for 2 h. The 2 reaction mixtures were then combined and stirred at room temperature for 18 h. The resulting solution was then filtered and washed with HCl (1M), sodium bicarbonate then brine. The organic layers were combined and dried over MgSO4 and evaporated to dryness. The crude mixture was purified using flash chromatography (0-100% ethyl acetate in hexane), to yield a cream oil. 225 mg, (63%), LCMS tr=1.96 min (50% MeOH and 50% water at 0.5 ml/min), m/z M+H 194.16, HPLC tr=1.82 min (Isocratic 90% acetonitrile and 10% water at 1.0 ml/min), 100%, 1HNMR (CDCl3, 270 MHz) δ 2.41 (4H, t, J=6.2 Hz, CH2), 3.85 (4H, t, J=6.2 Hz, CH2), 6.50 (1H, dd, J=1.0, 2.0 Hz, ArH), 7.37 (1H, t, J=1.7 Hz, ArH), 7.68 (1H, dd, J=1.0, 1.7 Hz, ArH).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][CH:16]([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:23]([CH2:22][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH:16]([F:15])[F:26])=[CH:25][CH:24]=1)[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1CBr
Reactant: NCc1ccc(OC(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2c(Cl)cc(Cl)cc2CN1Cc1ccc(OC(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
A mixture of 2-Bromomethyl-4,6-dichloro-benzoic acid methyl ester (0.150 g, 0.5 mmol), 4-difluoromethoxy-benzyl amine (0.101 g, 0.6 mmol), and K2CO3 (0.138 g, 1.0 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography of the product using 30% ethyl acetate in hexane afforded 5,7-dichloro-2-(4-difluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.036 g, 20%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.22 (s, 2H), 4.74 (s, 214), 6.49 (t, 1H) 7.11 (d, 2H), 7.26-7.32 (m, 3H), 7.42 (s, 1H). GC-MS: m/z 357 (M)+.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[N:19]1([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]3[C:33]([C:52]4[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([F:61])([F:60])[F:59])[CH:53]=4)=[N:34][C:35]4[C:40]([C:41]=3[C:42](O)=[O:43])=[CH:39][C:38]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])=[C:37]([O:50][CH3:51])[CH:36]=4)[CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[F:62][C:63]([F:73])([F:72])[C@@H:64]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[NH2:65].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.ClCCl.C([O-])(O)=O.[Na+]>[N:19]1([CH:25]2[CH2:26][CH2:27][N:28]([CH2:31][C:32]3[C:33]([C:52]4[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([F:59])([F:61])[F:60])[CH:53]=4)=[N:34][C:35]4[C:40]([C:41]=3[C:42]([NH:65][C@H:64]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[C:63]([F:72])([F:73])[F:62])=[O:43])=[CH:39][C:38]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])=[C:37]([O:50][CH3:51])[CH:36]=4)[CH2:29][CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCS(=O)(=O)c1cc2c(C(=O)O)c(CN3CCC(N4CCCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)c1cc2c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c(CN3CCC(N4CCCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide, 0.253 mL of a 50% solution in ethyl acetate, 0.425 mmol) was added to a solution of 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.200 g, 0.304 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.069 g, 0.395 mmol), N,N-diisopropylethylamine (10.60 μL, 0.061 mmol) in dichloromethane (2 mL) at 0° C. The mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred overnight. The reaction mixture was diluted with saturated NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in DMSO and purified via HPLC (Waters, Sunfire, 30×75 mm column, 50 mL/min, 20-60% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated to afford 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.160 g, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.05 (br. s., 1H), 8.50 (br. s., 1H), 7.97 (br. s., 1H), 7.87 (d, J=7.53 Hz, 2H), 7.80 (s, 1H), 7.71-7.78 (m, 1H), 7.65 (br. s., 2H), 7.42-7.51 (m, 3H), 6.22 (quin, J=8.60 Hz, 1H), 4.10 (s, 3H), 3.40-3.61 (m, 3H), 3.12-3.27 (m, 1H), 2.05-2.44 (m, 6H), 1.58-1.82 (m, 2H), 1.03-1.52 (m, 12H), 0.77-1.00 (m, 2H); MS (m/z) 777.2 (M+H+).