Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH2:7][CH:8]1[C:22](=[O:23])[C:12]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:15][C:11]=2[CH2:10][CH2:9]1)C>C(O)C.[NH4+].[Cl-]>[OH:23][CH:22]1[C:12]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:15][C:11]=2[CH2:10][CH2:9][CH:8]1[CH2:7][CH2:6][OH:5]
Reactant: CCOC(=O)CC1CCc2onc(-c3ccccc3)c2C1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: OCCC1CCc2onc(-c3ccccc3)c2C1O
Temperature: 25 °C
Yield: 100 %

Procedure:
In a 2 liter round-bottomed flask was dissolved 4,5,6,7-tetrahydro-4-oxo-3-phenyl-1,2-benzisoxazol-5-acetic acid ethyl ester (3.0 g) in absolute ethanol (300 ml) at room temperature. Sodium borohydride (6.07 g) was added and the solution was heated to reflux. The solution was cooled to room temperature, then diluted with saturated NH4Cl until a solid appeared. The reaction mixture was basified to pH 9 using 10% NAOH (aq.). The product, an oil, was extracted with ether and the aqueous phase was extracted twice with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to give 2.60 g of 4-hydroxy-5-(2-hydroxyethyl)-3-phenyl-4,5,6,7-tetrahydro-1,2-benzisoxazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=1>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:22][CH:23]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCc1nc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: Nc1ccc(CCCO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(Nc2ccc(CCCO)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 75 °C
Yield: 35.4 %

Procedure:
2-Chloro-4-(3-chlorophenyl)-6-ethyl-1,3,5-triazine (0.150 g, 0.59 mmol) and 3-(4-aminophenyl)propan-1-ol (0.130 g, 0.89 mmol) were suspended in acetic acid (5 mL). The mixture was heated to 75° C. for 2 h. After this time, the reaction was cooled, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.077 g, 35%) as a yellow solid. MW=368.86. 1H NMR (DMSO-d6, 500 MHz) δ 10.19 (s, 1H), 8.41-8.31 (m, 2H), 7.71-7.67 (m, 3H), 7.60 (t, J=8.0 Hz, 1H), 7.24-7.16 (m, 2H), 4.45 (t, J=5.5 Hz, 1H), 3.43 (q, J=5.5 Hz, 2H), 2.77 (q, J=7.5 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H), 2.51-2.49 (m, 2H), 1.75-1.69 (m, 2H), 1.32 (t, J=7.5 Hz, 3H); APCI MS m/z 369 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[F:19][C:20]([F:29])([F:28])[C:21]([O:23]C(C)(C)C)=O.[C:30]1([CH2:36][C:37](=[N:39]O)[NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>O1CCCC1>[F:29][C:20]([F:19])([F:28])[C:21]1[O:23][N:38]=[C:37]([NH2:39])[C:36]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)C(F)(F)F
Reactant: NC(Cc1ccccc1)=NO
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Nc1noc(C(F)(F)F)c1-c1ccccc1
Temperature: -75 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
Under a nitrogen atmosphere, dry tetrahydrofuran (90 ml) was added to diisopropylamine (14.5 ml, 0.105 mole, 5.23 mole) and then to the solution was added a 15% solution of butyllithium in n-hexane (64 ml, 0.100 mole, 5.0 eq.) with cooling below 0° C. After keeping the mixture at 0° C. for 30 minutes, it was cooled at -75° C. The mixture of t-butyl trifluoroacetate (10.21 g, 0.0600 mole, 3 eq.), phenylacetamide oxime (3.00 g, 0.0200 mole) and dry tetrahydrofuran (45 ml) was added dropwise, keeping the mixture below -72° C. After the mixture was stirred at -75° C. for 1 hour, it was allowed to warm to room temperature over 1 hour. To the mixture was added 10% hydrochloric acid (90 ml, 0.246 mole) and refluxed for 2.5 hours. The reaction mixure was distilled under reduced pressure to remove tetrahydrofuran and n-hexane. The resulting residue was adjusted above pH 13 with a 48% solution of sodium hydroxide and extracted with methylene chloride. After the extract was dried with anhydrous sodium sulfate, the solvent was distilled off. The resulting residue was purified by column chromatography on alumina and silica gel to give the title compound (0.60 g, 13.1%). This product was recrystallized from cyclohexane to give colorless needles, m.p. 92.0°-93.0° C. The structure of this compound was confirmed by IR, NMR and UV.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10](Cl)[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C=O)C.[CH2:25]([O:27][CH2:28][CH2:29][CH2:30][OH:31])[CH3:26]>>[NH2:2][C:3]1[N:11]=[C:10]([O:31][CH2:30][CH2:29][CH2:28][O:27][CH2:25][CH3:26])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CCOCCCO
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOCCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 120 °C
Yield: 76 %

Procedure:
To sodium (150 mg, 6.5 mmol) in 5 ml of 3-ethoxypropanol were added 6-amino-9-benzyl-2-chloropurine (500 mg, 1.93 mmol) and DMF (10 ml). The mixture was heated at 120° C. for 1 hour. The reaction mixture was concentrated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and the solvent was removed. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (481 mg, yield 76%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.Cl>CO>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of serine methyl ester hydrochloride (0.12 g, 0.78 mmol) in 1.6 ml of dry MeOH, at room temperature, under argon, were added successively triethylamine (10% solution, 0.16 ml) and (BOC)2O (0.19 g, 1.1 eq.) and the solution was stirred for 60 minutes. It was then poured in cold 2% HCl and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4, the solids were filtered and the solvents evaporated to give 0.17 g (100%) of the titled compound as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.C1C(=O)N([I:18])C(=O)C1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[I:18][C:3]1[C:4]2[N:8]=[CH:7][NH:6][C:5]=2[CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc2[nH]cnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc2[nH]cnc2c1I
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A solution of 5-methyl-1H-benzoimidazole (132 mg, 1.0 mmol) and NIS (248 mg, 1.10 mmol) in 1 mL of TFA was reflux for 1 hr and then cooled to RT. Treated with 30 mL of EtOAc, the mixture was neutralized with sat. NaHCO3 solution. The organic layer was washed with H2O (10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5% MeOH/CH2Cl2) gave 78 mg (30%) of product as a white solid: 1H-NMR (CDCl3; 400 MHz) δ 8.07 (d, 1H), 7.57 (br s, 1H), 7.22 (d, 1H, J. 8.4 Hz), 2.59 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C8H7IN2, 259.0 (M+H), found 259.2.
Reaction SMILES: C([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:35])[N:13]([C@@H:19]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:20]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[O:21])[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][NH:22][C:20](=[O:21])[C@@H:19]([N:13]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:12]([NH:11][CH2:10][CH2:9][OH:8])=[O:35])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)CCN(C(=O)NCCOCc1ccccc1)[C@@H](Cc1ccccc1)C(=O)NCCN(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCN(C(=O)NCCO)[C@@H](Cc1ccccc1)C(=O)NCCN(C)C
Reaction time: 4.5 h
Yield: 68 %

Procedure:
Under a nitrogen atmosphere, 20% palladium hydroxide on carbon (30 mg) is added to a solution of (2S)-2-[3-[2-(benzyloxy)ethyl]-1-isoamylureido]-N-[2-(dimethylamino)ethyl]-3-phenylpropionamide (Compound No. 21-1, 300 mg) in methanol (10 ml). The mixture is stirred under a hydrogen atmosphere for 4.5 hours. Palladium hydroxide on carbon is filtered out with Celite, and the filtrate is concentrated under reduced pressure. The concentrate is dissolved in ethyl acetate. The solution is washed with a 10% aqueous sodium hydrogencarbonate solution, water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 167 mg (68%) of the titled compound (Compound No. 22-1).
Reaction SMILES: C(O)(=O)C.[C:5]([C:7]([C:26]#[N:27])([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][CH2:11]1)#[N:6]>O>[C:5]([C:7]([C:26]#[N:27])([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]1)#[N:6]
Reactant: N#CC(C#N)(CCC1CCC2(CC1)OCCO2)CCC(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: N#CC(C#N)(CCC1CCC(=O)CC1)CCC(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To 20 mL of a 50% aqueous acetic acid solution, 1.85 g of 8-(3,3-dicyano-6,6,6-trifluorohexyl)-1,4-dioxaspiro[4.5]decane was added, followed by stirring at 50° C. for 8 hours under a nitrogen atmosphere. To the reaction mixture was added 100 mL of water, followed by extraction twice with 100 mL of ethyl acetate. The combined organic layer was washed sequentially with 100 mL of a saturated aqueous sodium hydrogen carbonate solution and 100 mL of a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.37 g of 4-(3,3-dicyano-6,6,6-trifluorohexyl)cyclohexanone represented by the following formula:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CCC([O-])(C)C.[Na+].ClCCl.C1(C)C=CC=CC=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:14]([O:13][C:11]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([N:21]3[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]3)=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)C1(c2ccc(Br)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3(C(=O)OC(C)(C)C)CC3)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (297.2 mg, 0.001000 mol), tert-butyl piperazine-1-carboxylate (186.2 mg, 0.001000 mol), sodium tert-pentoxide (110.1 mg, 0.001000 mol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (24.5 mg, 0.0000300 mol) and 1,1′bis(diphenylphosphino)ferrocene (16.6 mg, 0.0000300 mol) was deaerated and then charged with nitrogen. To the mixture was added toluene (3.0 mL, 0.028 mol), and the resulting mixture was heated at 100° C. overnight. The mixture was poured into ice-water and was extracted with ethyl acetate (4×10 mL). The combined organic layer was washed with water and brine successively, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combiflash with ethyl acetate/heaxane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18](Cl)[C:19]4[S:20][CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:23]=4)[CH:16]=3)[NH:11][C:10](=[O:31])[C:9]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:5]=[CH:6][CH:7]=1.[C:37]1([C:43]2[NH:44][CH:45]=[CH:46][N:47]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([N:44]4[CH:45]=[CH:46][N:47]=[C:43]4[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:19]4[S:20][CH:21]=[C:22]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:23]=4)[CH:16]=3)[NH:11][C:10](=[O:31])[C:9]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2)c2cc(C(Cl)c3nc(-c4ccccc4)cs3)ccc2[nH]c1=O
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1c(-c2cccc(Cl)c2)c2cc(C(c3nc(-c4ccccc4)cs3)n3ccnc3-c3ccccc3)ccc2[nH]c1=O
Temperature: 60 °C
Yield: 5.1 %

Procedure:
A mixture of intermediate (20) (0.0245 mol), 2-phenyl-1H-imidazole (0.0368 mol) and K2CO3 (0.0735 mol) in acetonitrile (150n) was stirred at 60° C. The solvent was evaporated till dryness. The residue was taken up in DCM and water. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.8 g (5.1%) of ethyl 4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-[(2-phenyl-1H-imidazol-1-yl)(4-phenyl-2-thiazolyl)methyl]-3-quinolinecarboxylate.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[N:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:11]=[N:10][C:9]=2[CH:21]([CH3:23])[CH3:22])=[CH:4][C:3]=1[CH3:26].[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[CH:37])=[CH:32][CH:31]=1.C(N(CC)CC)C>CN(C=O)C.[O-]S(C(F)(F)F)(=O)=O.[Zn+2].[O-]S(C(F)(F)F)(=O)=O>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:2]2[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]3[N:12]([C:13]4[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=4[Cl:20])[N:11]=[N:10][C:9]=3[CH:21]([CH3:22])[CH3:23])=[CH:4][C:3]=2[CH3:26])=[CH:32][CH:31]=1
Reactant: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1Br
Reactant: C#Cc1ccc(C(=O)OC)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a room temperature solution of 5-(4-bromo-3-methyl-phenoxymethyl)-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-[1,2,3]triazole (50 mg, 0.110 mmol) in DMF (1 mL) are added 4-ethynyl-benzoic acid methyl ester (18 mg, 0.110 mmol) and triethylamine (107 μL, 0.770 mmol). The reaction mixture is degassed for 20 minutes with nitrogen. To the reaction mixture are added dichloro(bistriphenylphosphine) palladium (II) (8 mg, 0.011 mmol, 10 mol %) and zinc (II) triflate (40 mg, 0.110 mmol). The reaction mixture is heated to 80° C. After 3 h, the reaction is concentrated and the residue is chromatographed (40 g SiO2, 0% to 5% EtOAc/Hexanes) to yield 4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenylethynyl}-benzoic acid methyl ester (38 mg, 64%). LC/MS m/e 534.2 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:24].C(N(CC)C(C)C)(C)C.[Cl:34][C:35]([Cl:40])([Cl:39])[C:36](Cl)=[O:37].C(OCC)C>ClCCl>[Cl:34][C:35]([Cl:40])([Cl:39])[C:36]([C:19]1[N:11]2[C:10]([CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:22]=[CH:23][C:2]([I:1])=[C:3]([CH3:24])[CH:4]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12]2)=[CH:21][CH:20]=1)=[O:37]
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1I
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1I
Temperature: 25 °C
Reaction time: 23 h
Yield: 77627.2 %

Procedure:
To a solution of 10-(4-iodo-3-methylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (5.0 g, 0.0117 mmol) and N,N-diisopropylethylamine (3.25 mL, 0.0187 mol) in dry dichloromethane (50 mL) at room temperature under nitrogen was added dropwise trichloroacetyl chloride (1.95 mL, 0.0175 mol) and the reaction mixture was stirred at room temperature for 23 hours. Additional N,N-diisopropylethylamine (1.02 mL, 0.00583 mol) and trichloroacetyl chloride (0.65 mL, 0.00583 mol) were added and stirring continued at room temperature for 4 hours. The reaction mixture was then partitioned between dichloromethane (200 mL) and 2 M hydrochloric acid (200 mL). The organic phase was separated, washed with 2 M hydrochloric acid (200 mL) and water (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a black syrup. Purification by flash chromatography using a solvent gradient of 10 to 15% ethyl acetate in hexane gave an orange foam. Diethyl ether (100 mL) was added and the resulting suspension stirred vigorously for 4 hours then filtered to afford the title compound (5.21 g, 78%) as an off-white solid, m.p. 163° C.
Reaction SMILES: [C:1](/[C:3](=[CH:9]/OCC)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[NH2:2][C:1]1[N:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[N:23]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCO/C=C(/C#N)C(=O)OCC
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(OC)cc2)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (Z)-ethyl 2-cyano-3-ethoxyacrylate (9.64 g, 57.0 mmol), 4-methoxyphenylhydrazine hydrochloride (9.95 g, 57.0 mmol) and Na2CO3 (6.04 g, 57.0 mmol) in EtOH (480 mL) was refluxed for 5 h and stirred overnight at rt. The insoluble material was filtered off and the filtrate was concentrated and solid precipitated. The precipitate was collected and washed with MeOH and washed with water extensively. The pale solid was dried to provide the desired product: 1H NMR (400 MHz, DMSO-D6) δ ppm 7.65 (1H, s), 7.42 (2H, d), 7.07 (2H, d), 6.15 (2H, s), 4.14-4.26 (2H, m), 3.81 (3H, s), 1.27 (3H, t).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[CH2:38][CH2:39][OH:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:26]2[CH2:25][CH2:24][C:22]3([O:21][CH2:20][CH2:19][N:18]([C:16]([C:14]4[N:15]=[C:11]([CH:8]([CH3:10])[CH3:9])[S:12][CH:13]=4)=[O:17])[CH2:23]3)[CH2:28][CH2:27]2)=[CH:32][C:31]=1[CH2:38][CH2:39][OH:40]
Reactant: O=Cc1ccc(Cl)c(CCO)c1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(Cl)c(CCO)c4)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
A solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.178 g) in NMP (2 mL) was treated with acetic acid (0.032 mL) and stirred for 5 minutes. A solution of 4-chloro-3-(2-hydroxyethyl)benzaldehyde (example 75, step c) (0.154 g) in NMP (3 mL) was then added, the resulting solution was stirred for 1 hour and was then treated with sodium triacetoxyborohydride (0.181 g) and stirred overnight at room temperature. More sodium triacetoxyborohydride (0.404 g) was added and the mixture was stirred for an additional 6 hours, then poured into saturated sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 1:2:97 triethylamine:methanol:dichloromethane to afford the subtitled compound as a colourless gum. Yield 0.157 g.
Reaction SMILES: C[O:2][C:3](=[O:47])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([O:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:22])[CH:18]=3)[N:13]([C:29](=[O:44])[NH:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:12]=2)=[C:6]([O:45][CH3:46])[CH:5]=1.O1CCCC1.CO.O.[OH-].[Li+]>O>[CH:31]([NH:30][C:29]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([NH:20][C:21]([O:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:22])=[CH:16][CH:15]=2)[C:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:47])=[O:2])=[CH:5][C:6]=2[O:45][CH3:46])=[CH:12]1)=[O:44])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(Cc2cn(C(=O)NC(c3ccccc3)c3ccccc3)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(=O)NC(c2ccccc2)c2ccccc2)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
To a solution of 4-[1-(benzhydryl-carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (0.58 grams, 0.92 mmol) in 2:2:1 ratio of tetrahydrofuran:methanol:water (30 mL) was added lithium hydroxide monohydrate (0.19 grams, 4.50 mmol). The resulting solution was stirred at room temperature for 12 hours and then concentrated in vacuo. The crude product was treated with 1 M hydrochloric acid (aq), and the resulting precipitate collected via filtration to give 4-[1-(benzhydryl-carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (0.514 grams, 91% yield).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8][CH2:7]1)=[O:5].[CH3:21][Mg]I>C1COCC1>[C:4]([C@@H:6]1[CH2:7][CH2:8][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:10][CH2:11]1)(=[O:5])[CH3:21]
Reactant: C[Mg]I
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of tert-butyl cis-4-(methoxy(methyl)carbamoyl)cyclohexylcarbamate (4.7 g, 16.41 mmol) in THF (109 mL) was cooled to 0° C. under nitrogen atmosphere. To this was added methylmagnesium iodide (3M in ether solution)(10.94 mL, 32.8 mmol) dropwise via syringe, and the mixture was stirred at 0° C. for 1 hour. The ice bath was removed, and the reaction mixture was stirred for 18 hours at RT. The reaction mixture was again cooled to 0° C. under nitrogen atmosphere and quenched with aqueous NH4Cl (100 mL). DCM (200 mL) was added, and the layers were separated. The organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated to afford a yellow oil which was purified by silica gel chromatography (5-30% MeOH/DCM) to afford tert-butyl cis-4-acetylcyclohexylcarbamate as an off-white solid (1.8 g, 45.4% yield).