Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]([CH:35]([CH3:37])[CH3:36])[C:12]2[O:16][C:15]([C:17]3[CH:33]=[CH:32][C:20]([C:21]([NH:23][CH2:24][C@H:25]4[O:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:22])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:34]=1)#[N:8].Cl[C:39]1[N:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=1>CO>[C:7]([C:9]1[CH:10]=[C:11]([CH:35]([CH3:37])[CH3:36])[C:12]2[O:16][C:15]([C:17]3[CH:33]=[CH:32][C:20]([C:21]([NH:23][CH2:24][C@H:25]4[O:31][CH2:30][CH2:29][N:28]([C:39]5[N:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=5)[CH2:27][CH2:26]4)=[O:22])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:34]=1)#[N:8]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CCNCCO4)cc3)oc12
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CCN(c5nccc(C(F)(F)F)n5)CCO4)cc3)oc12
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a mixture of 48 mg of potassium carbonate in methanol (3 ml) was added 37 mg of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-[(7S)-1,4-oxazepan-7-ylmethyl]benzamide (INTERMEDIATE 20) followed by 2-chloro-4-(trifluoromethyl)pyrimidine (16 mg). The mixture was heated via microwave at 120° C. for 35 min, and then cooled and added directly to a 40M samplet for purification via column chromatography on a Biotage Horizon 40M column, eluting with 1 column volume of 100% hexanes, followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volumes, followed by 4 column volumes of 100% ethyl acetate, to provide the title compound (37 mg, 76%). Mass spectrum (ESI) 565.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.52 (s, 1H), 8.35 (d, J=8.5 Hz, 2H), 7.96 (d, J=8.3 Hz, 2H), 7.95 (s, 1H), 7.54 (s, 1H), 6.81 (d, J=4.8 Hz, 1H), 6.65 (bs, 1H), 4.26 (m, 2H), 3.98 (m, 3H), 3.70 (s, 2H), 3.69 (m, 2H), 3.48 (sept, J=7.0 Hz, 1H), 3.25 (m, 1H), 2.19 (m, 1H), 1.83 (m, 1H), 1.48 (d, J=7.1 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.C(=O)(OC(C)(C)C)[O:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C1COCC1>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(NCCN(C)C)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N(CCN(C)C)C(=O)OC(C)(C)C)cc1
Yield: 73.8 %

Procedure:
Methyl 4-(2-[dimethylamino]ethylamino)benzoate (1.00 g, 4.50 mmol) was dissolved in THF (30 ml). (2-Methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (1.035 g, 4.72 mmol) was added and the solution was refluxed for 3 h. The solvent was then evaporated, the residue was dissolved in DCM, washed with sat. aq. ammonium chloride solution, dried over sodium sulphate, filtered and evaporated to give methyl 4-[2-dimethylaminoethyl-[tert-butoxycarbonyl]amino]benzoate (1.07 g, 74%) as a brown oil.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.CO.[NH4+:12]>>[NH2:12][CH2:3][C@H:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[OH:1]
Reactant: [NH4+]
Reactant: c1cncc([C@H]2CO2)c1
Solvent: CO
Product: NC[C@@H](O)c1cccnc1

Procedure:
The title compound was prepared from 3-[(2S)-oxiranyl]pyridine (which was obtained in Example 129) and saturated ammonium methanol in substantially the same manner, as described in Example 124. The product was obtained as a brown oil; 1H NMR (400 MHz, DMSO-d6) δ 1.60 (brs, 2 H), 2.59–2.71 (m, 2 H), 4.47–4.50 (m, 1 H), 5.20 (brs, 1 H), 7.31–7.34 (m, 1 H), 7.68–7.71 (m, 1 H), 8.42–8.43 (m, 1 H), 8.50–8.51 (m, 1 H); MS (ES) m/z: 139 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=O)=[CH:30][CH:29]=4)[CH3:21])[C:14]=3[Cl:44])[C:5]2=[N:4][C:3]=1[CH3:45].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][C:31]([N:34]5[C:38](=[O:40])[CH2:37][CH2:36][C:35]5=[O:41])=[CH:30][CH:29]=4)[CH3:21])[C:14]=3[Cl:44])[C:5]2=[N:4][C:3]=1[CH3:45]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)CCC(=O)O)cc4)c3Cl)cccn2c1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N5C(=O)CCC5=O)cc4)c3Cl)cccn2c1Br
Yield: 11.2 %

Procedure:
A suspension of 3-bromo-8-[3-[N-[4-(3-carboxypropionamido)cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (110 mg) and anhydrous sodium acetate (16 mg) in acetic anhydride (1.1 ml) was refluxed for 5 hours. After cooling, the solvent was removed in vacuo. The residue was dissolved in dichloromethane (5 ml) and washed with water, saturated sodium bicarbonate twice and brine. After dried over magnesium sulfate, the solvent was removed in vacuo. The residue was purified by preparative thin-layer chromatography (ethyl acetate-methanol) to give 3-bromo-8-[2,6-dichloro-3-[N-[4-(succinimido)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (12 mg) as amorphous.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[N:31]=1>>[CH2:1]([CH:8]1[N:13]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[N:31]=2)[CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:24][CH2:25][CH2:26]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCNC(Cc4ccccc4)C3)ccc12
Reactant: O=[N+]([O-])c1cccc(Cl)n1
Product: CCc1nn(C2CCC2)c2cc(N3CCN(c4cccc([N+](=O)[O-])n4)C(Cc4ccccc4)C3)ccc12

Procedure:
Prepared using the same procedure described in Example 410 from 6-(3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole and 2-chloro-6-nitro-pyridine to afford the intermediate 6-[3-benzyl-4-(6-nitro-pyridin-2-yl)-piperazin-1-yl]-1-cyclobutyl-3-ethyl-1H-indazole {20.5 mg; LC/MS (Method B) 5.09 min, [M+1]+ 497]}. The nitro-intermediate was reduced with sodium hydrosulfite (48 mg, 0.28 mmol) in 50:50 THF/water at room temperature to obtain the title compound as a tan solid (6 mg, 2% overall). LC/MS (Method B) 4.02 min, [M+1]+ 467.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: CCN1CCN(c2ccc(C=O)c(Cl)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CCN(c2ccc(CO)c(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The crude 2-chloro-4-(4-ethylpiperazin-1-yl)benzaldehyde was dissolved in anhydrous ethanol (20 mL). The solution was cooled to 0° C. under nitrogen, and NaBH4 (1.52 g, 40 mmol) was added in one portion. The mixture was stirred at room temperature for 2 hours and quenched by addition of water (5 mL). Na2SO4 (20 g) was then added. After 10 minutes, the mixture was filtered. The filtrate was evaporated to provide [2-chloro-4-(4-ethylpiperazin-1-yl)phenyl]methanol.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]([CH2:42][CH2:43][CH2:44]O)[CH2:30][N:31]([CH3:41])[S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:26]=[CH:27][CH:28]=1>C(#N)C>[Br:1][CH2:44][CH2:43][CH2:42][CH:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=1)[CH2:30][N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: BrBr
Reactant: CN(CC(CCCO)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CN(CC(CCCBr)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
Bromine was added to a solution of triphenylphosphine (41.4 mg, 0.158 mmol) in 0.50 mL of acetonitrile until the red color persisted, and a small additional quantity of triphenylphorsphine was then added to consume the excess bromine. A solution of N-(2-(3-chlorophenyl)-5-hydroxypentyl)-N-methylbenzenesulfonamide (38.7 mg, 0.105 mmol) in 0.3 mL of acetonitrile was added. After stirring for 1 h, the reaction was quenched by a solution of sodium sulfite (20 mg) dissolved in 1.0 mL of water. The mixture was diluted with 15 mL of sodium bicarbonate and extracted with 2×20 mL of ethyl acetate. The organic layers were washed with 15 mL of brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with of 10% ethyl acetate in hexane to give 23 mg the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:12]=1[CH3:13])[C:7]([O:9]CC)=[O:8].C(O)C.[OH-].[Na+].Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:12]=1[CH3:13])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(OC)ccc(Br)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Br)c(C)c1C(=O)O
Reaction time: 42 h

Procedure:
A mixture of 6A (9.8 g, 34.1 mmol), water (40 ml), ethanol (80 ml) and sodium hydroxide (2.7 g, 68.3 mmol) is heated under reflux with stirring for 42 hours. The reaction mixture is diluted with water (80 ml), acidified with concentrated hydrochloric acid and extracted with dichloromethane. The organic phase is separated and concentrated. The solid material is collected by filtration, washed with water and dried yielding off-white crystals, 5.4 g (61%), mp 81-83° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:4][N:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C>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.[Cu]I.CN(C=O)C>[CH:10]1([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(OCC2CC2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(OCC2CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of 2-bromo-5-(cyclopropylmethoxy)pyridine (1.145 g), bis(triphenylphosphine)palladium(II) dichloride (175 mg), copper(I) iodide (48 mg), trimethylsilylacetylene (737 mg), triethylamine (759 mg) and DMF (15 mL) was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water, and the mixture was filtered through celite. The aqueous layer was separated from the organic layer. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow oil (774 mg).
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[N:19]([C@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7]1)=[N+:20]=[N-:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N=[N+]=[N-])C1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
Crude product from example C4 is dissolved in dry DMF (180 mL). After addition of sodium azide (11.7 g; 180.0 mmol) the reaction mixture is stirred for three days at 60° C. After filtration the reaction mixture is concentrated under reduced pressure, diluted with dichloromethane, extracted with water, half saturated brine and dried over MgSO4. After column chromatography on silica gel (cyclohexane/AcOEt—9:1) 11.8 g of the title compound is obtained as pale yellow oil.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=O)[NH:19][C:18]3=[O:28])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36]>N1C=CC=CC=1>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[S:36])[NH:19][C:18]3=[O:28])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc12
Solvent: c1ccncc1
Product: O=c1[nH]c(=S)c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 37.4 %

Procedure:
To a mixture of 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-2,4-(1H,3H)-quinazolinedione (3.1 g) and phosphorus pentasulfide (6.1 g) was added pyridine (70 ml) and the mixture was stirred for 18 hours at 100° C. The reaction mixture was cooled and then concentrated in vacuo. To the residue was added water and the mixture was stirred and then resultant precipitates were collected by filtration and washed with water. To the precipitates was added chloroform and the mixture was stirred enough and then insoluble materials were filtered off. These insoluble materials were washed twice with chloroform and then whole chloroform layers were combined, washed with water and with saturated sodium chloride aqueous solution respectively, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by a column chromatography on silica gel (90 g) using 2% methanol in chloroform for elution to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-4-thioxo-3,4-dihydro-2(1H)-quinazolinone (1.2 g) as an amorphous material.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]([NH2:22])[CH3:21])[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]([NH:22][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH3:21])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(N)c1cc(Cl)cc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cc(Cl)cc(Cl)c1
Yield: 11 %

Procedure:
A mixture of 2,4-difluoro-nitrobenzene (3.13 mmol), 1-(3,5-dichlorophenyl)ethanamine (3.13 mmol) and N,N-diisopropylethylamine (6.3 mmol) were stirred at 45° C. in dry acetonitrile (25 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (11% yield). 1H NMR (400 MHz, CDCl3): δ 9.23 (s, 1H), 7.87 (t, 1H), 7.28 (s, 1H), 7.19 (s, 2H), 6.41 (t, 1H), 6.11 (d, 1H), 4.51 (m, 1H), 1.62 (d, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=1.[OH-].[Na+]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
Methyl 3-(4-(2-quinolinylmethyloxy)benzyl)benzoate (0.05 mol) is heated at reflux in a 9:1 mixture of ethanol and 0.5N aqueous NaOH (450 ml). After several hours the clear reaction is evaporated. The solid residue is taken up in water and acidified. The resulting crystalline product is isolated by filtration and dried by suction with a rubber dam to obtain 3-(4-(2-quinolinylmethyloxy)benzyl)benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.Cl>CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=Cc1ccccc1Br
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: OC(Cc1ccccc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
A solution of 2-bromobenzaldehyde (18.50 g) in dry ether (20 ml) was added dropwise to a stirred solution of benzylmagnesium chloride [prepared from benzyl chloride (12.64 g) and magnesium (2.68 g)] in dry ether (120 ml), a thick precipitate forming during the addition. The mixture was stirred for 1 hour at room temperature then poured into water, acidified with 2M hydrochloric acid, and extracted with ether. The extracts were washed with water, dried, concentrated and chromatographed using dichloromethane and petrol (1:1) as eluant to give 1-(2-bromophenyl)-2-phenylethan-1-ol (10.95 g, 40%) as a white solid, melting point 84°-85° C.
Reaction SMILES: [C:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)(=O)[CH2:2][CH2:3][CH3:4].[CH:17]([NH2:19])=[O:18]>C(O)=O>[CH:17]([NH:19][CH:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4])=[O:18]
Reactant: CCCC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: NC=O
Solvent: O=CO
Product: CCCC(NC=O)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of the ketone produced as described above (21 g) and 98% formic acid (6 ml) was added over a period of one and a half hours to formamide (15 ml) at 160° C. After completion of the addition the temperature was raised to 180° to 185° C. and maintained in this range for five hours. The mixture was cooled and extracted with chloroform to yield a thick gum which on heating with petroleum ether (b.p. 60°-80°) gave a colourless solid which was recrystallised from petroleum ether (b.p. 60°-80°) to yield N-formyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine (m.p. 97.5° to 98.5° C.) (Formula I R1 =propyl; R2 =H; R3 =H; R4 =CHO; R5 =4--Cl; R6 =H).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C[O:33][C:34](=[O:48])[C@@H:35]([NH2:47])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=1>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26]([NH:47][C@@H:35]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=4)[C:34]([OH:33])=[O:48])=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N[C@@H](Cc4ccc(C(F)(F)F)cc4)C(=O)O)nc(CC4CCCC4)c3c2)cc1
Yield: 94.8 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 419) was reacted with (2S)-amino-3-(4-trifluoromethyl-phenyl)-propionic acid methyl ester HCl (38.4 mg, 0.14 mmol) as described in general procedure A. The resulting ester was hydrolyzed as described in general procedure C to afford 70.4 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:23][NH:24][C:25](=[O:31])[CH:26]([F:30])[C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:23][NH:24][C:25](=[O:31])[CH:26]([F:30])[C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: O=C(O)C(F)C(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CN1C(=O)C(NC(=O)C(F)C(=O)NCc2cc(F)cc(F)c2)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=468.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-fluoro-malonamic acid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][NH:5][CH2:6][CH:7]([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].[OH-].[Na+:19].CC(O)C.[C:24](=[S:26])=[S:25]>>[CH2:12]([CH:7]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:6][N:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:14][CH2:15][CH2:16][CH3:17])[C:24](=[S:25])[S-:26])[CH3:13].[Na+:19]
Reactant: CCCCC(CC)CNCC(CC)CCCC
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=S)[S-]

Procedure:
50.0 grams (0.207 mol) of di(2-ethylhexyl)amine, 16.9 grams of a 50 wt % NaOH solution (0.211 mol NaOH), and 60 mL reagent 2-propanol were combined in a 250 mL 3-neck round bottom reaction flask equipped with an overhead stirrer, a thermocouple probe, a reflux condenser, a Clasien adapter and a 25 mL addition funnel. 12.7 mL (0.211 mol) carbon disulfide was charged into the addition funnel. Carbon disulfide was added dropwise over a 30 minute period. The reaction temperature was maintained at 20-25° C. over the course of the CS2 addition. The product was post-reacted at 25° C. for six hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([C:10]1[S:11][C:12]([S:33][CH3:34])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:25]=3[NH2:32])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:43][S:44]([CH2:47][CH2:48][CH2:49][C:50](Cl)=[O:51])(=[O:46])=[O:45]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([C:10]1[S:11][C:12]([S:33][CH3:34])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:25]=3[NH:32][C:50](=[O:51])[CH2:49][CH2:48][CH2:47][S:44]([CH3:43])(=[O:46])=[O:45])[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)=[NH:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(Cl)cc2N)c1
Reactant: CS(=O)(=O)CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(Cl)cc2NC(=O)CCCS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
{[4-(2′-Amino-4′-chloro-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (120 mg, 0.22 mmol, Example 135, e) and Et3N (0.91 μL, 0.65 mmol) were dissolved into DCM (4 mL). To this was added (4-Methanesulfonyl-butyryl chloride (0.144 M, 3.1 mL, 0.44 mmol, Example 209: a) and the reaction was stirred at RT overnight. The solvents were removed in vacuo followed by purification by flash column chromatography (20% EtOAc/hexanes) that yielded the title compound as an orange solid (124 mg, 81%). ESI-MS (m/z): Calcd. for C29H34ClN3O7S4: 700.1 (M+1) found: 700.1.