Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([CH3:50])=[CH:48][C:47]([C:51](OC)=[O:52])=[N:46]2)=[CH:31][CH:30]=1.CN>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([CH3:50])=[CH:48][C:47]([C:51]([NH:2][CH3:1])=[O:52])=[N:46]2)=[CH:33][CH:34]=1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: COC(=O)c1cc(C)n(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1
Agent: CN
Product: CNC(=O)c1cc(C)n(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-5-methyl-1H-pyrazole-3-carboxylate and methylamine. M/e+ 381 for C20H19ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.20 (d, J=6.9 Hz, 1H), 7.68 m, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.28 (m, 1H), 6.86 (td, J=6.9, 1.1 Hz, 1H), 6.62 (m, 1H), 6.52 (s, 1H), 5.64 (s, 2H), 2.93 (d, J=5.1 Hz, 3H), 1.99 (s, 3H) ppm.
Reaction SMILES: [OH-].[Li+].C[N:4]([C:9](=[O:30])[C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:27])=[C:20]([Br:28])[CH:19]=2)=[C:12]([Cl:29])[CH:11]=1)[CH2:5][C:6]([OH:8])=[O:7].Cl>O1CCCC1>[Cl:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([Cl:29])[C:13]=1[O:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:27])=[C:20]([Br:28])[CH:19]=1)[C:9]([NH:4][CH2:5][C:6]([OH:8])=[O:7])=[O:30]
Reactant: CC(C)c1cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc(Br)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1cc(Oc2c(Cl)cc(C(=O)NCC(=O)O)cc2Cl)cc(Br)c1O
Reaction time: 16 h

Procedure:
Lithium hydroxide (1 N, 9 mL) was added at room temperature to a mixture of methyl-N-[3,5-dichloro-4-(3-bromo-4-hydroxy-5-isopropylphenoxy)benzoyl]glycine (150 mg, 0.305 mmol) and tetrahydrofuran (9 mL). After 16 hours, the reaction mixture was acidified with hydrochloric acid (1 N) and extracted with ethyl acetate. Filtration through a pad of silica gave N-[3,5-dichloro-4-(3-bromo-4-hydroxy-5-isopropylphenoxy)benzoyl]-glycine in quantitative yield as a light yellow solid. LC-MS (ES−1): m/z 476.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].CC1C=CC(S(O)(=O)=O)=CC=1.[OH:16][C@@:17]1([CH3:37])[CH2:22][CH2:21][C@H:20]2[C@H:23]3[C@H:33]([CH2:34][CH2:35][C@:18]12[CH3:19])[C@:31]1([CH3:32])[C@H:26]([CH2:27][C:28](=O)[CH2:29][CH2:30]1)[CH2:25][CH2:24]3>C(Cl)Cl>[CH2:1]1[O:4][C:28]2([CH2:29][CH2:30][C@@:31]3([CH3:32])[C@@H:26]([CH2:25][CH2:24][C@@H:23]4[C@@H:33]3[CH2:34][CH2:35][C@@:18]3([CH3:19])[C@H:20]4[CH2:21][CH2:22][C@@:17]3([OH:16])[CH3:37])[CH2:27]2)[O:3][CH2:2]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C[C@]12CCC3(C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O)OCCO3

Procedure:
Ethylene glycol (20 ml.) and p-TSA (5 mg.) is added to 17β-hydroxy-17α-methyl-5α-androstan-3-one (sold by Steraloids, Inc., Wilton, N.H., 3.0 g.) in methylene chloride (20 ml.). The mixture is heated on a steam bath until most of the methylene chloride is removed. The remainder of the methylene chloride is removed on a rotary evaporator. The mixture is cooled and a small amount of a sodium bicarbonate solution and water are added and the mixture filtered. The filtered solids are washed and dried to give the title compound, NMR (CDCl3), 0.83, 0.84, 1.20 and 3.29δ.
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:30]1(B(O)O)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:1][C:2]1([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:38]3[C:39]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:28]=2)[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OB(O)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(O)cc2)C2(O)CCCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(Oc3cccc4ccccc34)cc2)C2(O)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl 4-[2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)ethyl]piperazine-1-carboxylate (120 mg, 0.30 mmol), naphthalene-1-boronic acid (54 mg, 0.31 mmol) in dry dichloromethane (2 mL) was added copper (II) acetate (19 mg, 0.10 mmol), triethylamine (71 □L, 0.51 mmol), and powdered 4 Å sieves (100 mg) was stirred at room temperature for 16 h, after which time the reaction was filtered through a pad of Celite®, which was washed with dichloromethane (20 mL), and concentrated in vacuo. The product was purified via Biotage Horizon (FLASH 25 S, silica, gradient from 10% EtOAc/hexane to 60% EtOAc/hexane) to yield tert-butyl 4-{2-(1-hydroxycyclohexyl)-2-[4-(1-naphthyloxy)phenyl]ethyl}piperazine-1-carboxylate as a colorless oil. MS (ESI) m/z 531; HRMS: calcd for C33H42N2O4+H+, 531.32173; found (ESI, [M+H]+), 531.3203.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=[C:9]1[S:13][CH:12]=[CH:11][S:10]1)[C:5]([O:7]C)=[O:6].[OH-].[K+].CO>CO>[CH3:1][O:2][C:3](=[O:14])[C:4](=[C:9]1[S:13][CH:12]=[CH:11][S:10]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(C(=O)OC)=C1SC=CS1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(C(=O)O)=C1SC=CS1
Yield: 89.9 %

Procedure:
(1,3-Dithiol-2-ylidene)malonic acid dimethyl ester (232 mg) prepared according to the procedure described in JP-76.48666, was suspended in methanol (0.1 ml) and 1N KOH/methanol (3.0 ml) was added. The reaction mixture was refluxed for 1 h and then concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution was adjusted to 2 with 1N HCl. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give the title compound (196 mg) as a pale yellow powder.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][C:13]1([CH3:29])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=2)[O:14]1.[CH:30]([S:33](Cl)(=[O:35])=[O:34])([CH3:32])[CH3:31].O>ClCCl>[CH3:19][C:17]1([CH3:18])[C:13]([CH3:29])([CH3:12])[O:14][B:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][S:33]([CH:30]([CH3:32])[CH3:31])(=[O:35])=[O:34])=[CH:22][CH:21]=2)[O:16]1
Reactant: CC1(C)OB(c2ccc(CCN)cc2)OC1(C)C
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: O
Product: CC(C)S(=O)(=O)NCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add DBU (0.79 mL, 5.3 mmol) to 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethylamine (0.5 g, 1.8 mmol, can be prepared from 4-bromophenyl acetonitrile) in dichloromethane and stir at room temperature. After 10 minutes, cool to 0° C. and add isopropylsulfonylchloride (0.22 mL, 1.95 mmol). After 30 minutes, allow to warm to room temperature. After 3 hours, pour into water and extract with dichloromethane. Wash the combined organics with 1N HCl, water, and brine, dry over magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by flash chromatography (silica gel), eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (ES−)=352.2 (M−1).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([CH2:13][C:14](OCC)=[O:15])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1>[C:6]1([C:5]2[NH:4][CH2:1][CH2:2][NH:3][C:14](=[O:15])[CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: c1ccncc1
Product: O=C1C=C(c2ccccc2)NCCN1
Temperature: 180 °C
Yield: 23.1 %

Procedure:
30 g ethylenediamine were added to 96 g ethyl benzoylacetate in 200 ml pyridine and the mixture was boiled under reflux for five hours. Then the pyridine was distilled off and the residue was heated to 180° C. for one hour. After cooling, 500 ml of dichloromethane were added, and the reaction mixture was heated to 40° C. until dissolution occurred. Precipitation with acetone yielded 21.7 g 7-phenyl-1,2,3,4-tetrahydro-1,4-diazepin-5-one having a melting point of 206-214° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Br[C:44]1[N:45]([CH3:49])[CH:46]=[CH:47][N:48]=1>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[N:45]([CH3:49])[CH:46]=[CH:47][N:48]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: Cn1ccnc1Br
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3nccn3C)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 2-bromo-1-methyl-1H-imidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].[C:13]1(=O)[O:18][C:16](=[O:17])[CH:15]2[CH2:19][CH2:20][CH:21]=[CH:22][CH:14]12.C(OCC)(=O)C.C(Cl)Cl>C(O)(=O)C>[F:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[N:1]1[C:13](=[O:18])[C:14]3[CH2:22][CH2:21][CH2:20][CH2:19][C:15]=3[C:16]1=[O:17])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1Cc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1
Yield: 77.4 %

Procedure:
A mixture of 6-amino-5-fluoro-2-indolinone (10.5 g, 63.25 mmol) and tetrahydrophthalic anhydride (10.95 g, 66.42 mmol) in acetic acid (30 mL) is heated at reflux for 2 hours, cooled and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 3:7 ethyl acetate/methylene chloride solution gives the title product as a light violet solid (14.7 g, mp 234°-236° C.). Following the procedure of Example 3, but substituting 6-amino-2-indolinone for 6-amino-5-fluoro-2-indolinone gives N-(2-oxo-6-indolinyl)-1-cyclohexene-1,2-dicarboximide as a green solid, mp 225°-226° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:34]=[CH:33][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]([OH:32])=[CH:26][C:27](=[O:31])[O:28]4)=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]([OH:32])=[C:26]([N+:1]([O-:4])=[O:2])[C:27](=[O:31])[O:28]4)=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:34]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2ccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cc2o1
Solvent: ClC(Cl)Cl
Product: O=c1oc2cc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)ccc2c(O)c1[N+](=O)[O-]

Procedure:
Fuming nitric acid (10 ml; d 1.52) was added dropwise over 15 mins to a cold (0° C.) stirred suspension of 1-(4-chlorobenzyl)-4-[3-(4-hydroxycoumarin-7-yloxy)propyl]piperazine (2.0 g) in chloroform (200 ml) and the mixture stirred for a further 1 hour at 0°. The solution which formed precipitated a yellow solid on addition of water which after filtration was washed with ethanol to give 2.62; (95%) of the dinitric acid salt of the title compound of m.p. 142°-144° (dec). νmax (mull) 2700 (br), 1740, 1615, 1525 cm-1. (Found; C, 45.87; H. 4.52; Cl, 5.66; N, 11.36; C23H24ClN3O6 2HNO3 requires; C, 46.05; H, 4.37; Cl, 5.91; N, 11.67%).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([Br:29])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)C.[OH-].[Na+]>O1CCCC1>[Br:29][C:21]1[CH:20]=[C:19]([S:16]([NH:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][C:14]3[N:6]([CH2:5][C:4]([OH:30])=[O:3])[N:7]=[CH:8][C:9]2=3)(=[O:18])=[O:17])[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of [(R)-4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (18.0 mg, 0.035 mmol) in tetrahydrofuran (2 mL) was added an aqueous solution of sodium hydroxide (1 N, 2 mL). The resulting mixture was stirred at room temperature for 2 hours, then extracted with diethyl ether (6 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and then stirred with diethyl ether (2 mL) and petroleum ether (6 mL) at room temperature for 2 hours. The resulting mixture was filtered to afford [(R)-4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid (13.3 mg, 78.8%) as a white powder. 1H NMR (400 MHz, CD3OD) δ ppm 8.34 (s, 1H), 8.20 (s, 2H), 6.81 (s, 1H), 4.80 (s, 2 H), 4.48 (t, 1H), 2.50 (m, 2H), 2.00-1.72 (m, 4H). MS calcd. for C16H15BrF3N3O4S 481, obsd. (ESI+) [(M+H)+] 482.
Reaction SMILES: [NH2:1][C:2]1[C:19]([C:20]#[CH:21])=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.I[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>>[NH2:1][C:2]1[C:19]([C:20]#[C:21][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: C#Cc1cc(C(=O)N=[S@@](C)(=O)c2ccccc2)cnc1N
Product: C[S@@](=O)(=NC(=O)c1cnc(N)c(C#Cc2ccc(O)cc2)c1)c1ccccc1
Yield: 62 %

Procedure:
In a manner similar to that describe in Example 467, (S)-6-amino-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-iodophenol are converted to the title compound (41 mg, 62%).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[C:13]([CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[C:25]([F:28])([F:27])[F:26])=[O:16])=[C:12]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:11]2[C:6](=[CH:7][C:8]3[C:37](=[O:38])[CH2:36][CH2:35][C:9]=3[CH:10]=2)[O:5]1.CO.Cl>COCCOC>[F:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:13]2[C:4](=[O:3])[O:5][C:6]3[C:11]([C:12]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:10][C:9]2[CH2:35][CH2:36][CH:37]([OH:38])[C:8]=2[CH:7]=3)=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:20]=1
Reactant: O=C(Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)C(=O)CC3)Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: O=C(Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)C(O)CC3)Nc1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
A suspension of NaBH4 (30 mg) in DME (2 ml) was combined with 2-(2,8-dioxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)-N-[4-fluoro-2-(trifluoromethyl)phenyl]-acetamide (Example 88) (170 mg) with cooling in ice, and further combined with methanol, and stirred at room temperature for 10 minutes. The reaction solution was poured into diluted hydrochloric acid, which was then extracted with ethyl acetate. The extract was washed with water, and then dried over magnesium sulfate, and concentrated under reduced pressure to obtain the title compound as a colorless crystal (110 mg, yield: 65%). An aliquot was recrystallized from ethyl acetate to measure a melting point. Melting point: 217-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]([CH3:15])[C:13](=[O:16])[C:12]([CH3:18])([CH3:17])[C:11]2=[O:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[NH4+].[CH2:22]1COCC1>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:11](=[O:19])[C:12]([CH3:18])([CH3:17])[C@:13]([OH:16])([CH3:22])[C@H:14]2[CH3:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: C[C@H]1N(c2ccc(C#N)c(Cl)c2)C(=O)C(C)(C)[C@@]1(C)O
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 2-chloro-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (90 mg) in THF (5 mL) was cooled to −78° C., methylmagnesium bromide-ether solution (0.22 mL, 3 mol/L) was added under a nitrogen atmosphere, and the reaction mixture was warmed to room temperature. The reaction mixture was again cooled to −78° C., a 3mol/L methylmagnesium bromide-ether solution (0.89 mL) was added, and the reaction mixture was warmed to room temperature. The reaction mixture was added to saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (yield: 29 mg, 30%).
Reaction SMILES: [CH2:1]1[O:6][CH:2]1[CH2:3][CH2:4][CH3:5].[CH2:7]([NH2:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>>[CH2:17]([NH:18][CH2:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:19][CH2:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5]
Reactant: NCCCCCCCCCCCN
Reactant: CCCC1CO1
Product: CCCC(O)CNCCCCCCCCCCCNCC(O)CCC

Procedure:
Condensation of 1-pentene oxide and 1,11-undecanediamine affords N,N'-(1,11-undecylene)-bis[2-hydroxypentylamine] (I: R = CH3 (CH2)2, R' = H, X = (CH2)11, Z = H).
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][S:20]([CH:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])(=[O:22])=[O:21])[CH:14]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>>[O:1]=[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][S:20]([CH:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])(=[O:22])=[O:21])[CH:14]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCC(CCC)S(=O)(=O)Nc1cccc(C(O)CCNC(=O)OC(C)(C)C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: CCCC(CCC)S(=O)(=O)Nc1cccc(C(=O)CCNC(=O)OC(C)(C)C)c1

Procedure:
Oxidation of tert-butyl 3-hydroxy-3-(3-(1-propylbutylsulfonamido)phenyl)propylcarbamate by PCC following the method used in Example 16 gives tert-butyl 3-oxo-3-(3-(1-propylbutylsulfonamido)phenyl)propylcarbamate.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=1)[CH2:51][NH2:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:52][CH2:51][C:50]4[CH:53]=[CH:54][CH:55]=[C:48]([Cl:47])[CH:49]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cccc(Cl)c1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2cccc(Cl)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with 3-chloro-benzylamine (Avocado) to give the title compound. HR-MS (ES, m/z) calculated for C43H49Cl3N5O3 [(M+H)+] 788.2896, observed 788.2890.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])[C:3]#[N:4].[ClH:16].C(O)=[O:18]>>[ClH:16].[NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]([F:15])([F:13])[F:14])[C:3]([NH2:4])=[O:18]
Reactant: N#CC(N)c1ccc(F)cc1C(F)(F)F
Reactant: O=CO
Agent: Cl
Product: NC(=O)C(N)c1ccc(F)cc1C(F)(F)F
Yield: 25 %

Procedure:
A solution of (RS)-amino-(4-fluoro-2-trifluoromethyl-phenyl)-acetonitrile (4.47 g) in formic acid (15 ml) saturated with hydrogen chloride was stirred at room temperature for 90 min. The mixture was then concentrated in vacuo and the residue was resuspended in acetone whereby white crystals formed The crystals were collected by filtration, washed with acetone and dried in vacuo to afford (RS)-2-amino-2-(4-fluoro-2-trifluoromethyl-phenyl)-acetamide hydrochloride (1.40 g, 25%) as a white solid. MS (ISP): 273.1 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([CH2:12][OH:13])[C:9]([CH3:14])=[C:8]2[C:4]=1[C:5]1[CH2:18][CH2:17][O:16][C:15]([CH2:22][C:23]([OH:25])=[O:24])([CH2:19][CH2:20][CH3:21])[C:6]=1[NH:7]2)#[N:2].Cl[CH:27](Cl)[CH3:28].C1C=CC=CC=1>CCOC(C)=O.O=[Mn]=O>[CH2:27]([O:24][C:23](=[O:25])[CH2:22][C:15]1([CH2:19][CH2:20][CH3:21])[C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH2:18][CH2:17][O:16]1)=[C:3]([C:1]#[N:2])[CH:11]=[C:10]([CH:12]=[O:13])[C:9]=3[CH3:14])[CH3:28]
Reactant: CC(Cl)Cl
Reactant: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(C)c(CO)cc(C#N)c21
Agent: O=[Mn]=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C=O)cc(C#N)c21
Temperature: 40 °C
Reaction time: 1.3 h
Yield: 96 %

Procedure:
To a solution of (5-cyano-7-hydroxymethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (8.28 g, 22 mmol) in dichloroethane/benzene (85 mL/85 mL) was added a homogeneous mixture of activated MnO2 (19.4 g, 223 mmol) and Celite (19.4 g). The solution was heated to 40° C. and agitated vigorously for 1.3 hours. The reaction was cooled, diluted with EtOAc and filtered through Celite. Concentration of the filtrate in vacuo afforded 7.88 g (96%) of a pale yellow foam. 1H NMR (CDCl3) δ 10.31 (bs, 1 H), 10.27 (s, 1H), 7.90 (s, 1H), 4.27 (m, 2H), 4.11 (m, 1H), 3.95 (m, 1H), 3.09 (m, 2H), 3.04 (d, J=17.0 Hz, 1H), 2.95 (d, J=7.6 Hz, 1H), 2.57 (s, 3H), 2.00 (m, 2H), 1.30 (m, 4H), 0.90 (t, J=7.62 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30](O)=[O:31])=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1.[O:47]1[CH2:51][CH2:50][C@@H:49]([NH2:52])[CH2:48]1>>[O:47]1[CH2:51][CH2:50][C@@H:49]([NH:52][C:30](=[O:31])[CH:29]([C:26]2[CH:27]=[CH:28][C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:34])[F:1])=[O:6])[CH:9]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)=[CH:24][CH:25]=2)[CH3:33])[CH2:48]1
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Reactant: N[C@@H]1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C(=O)N[C@@H]1CCOC1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and (3R)-tetrahydrofuran-3-amine 4-methylbenzenesulfonate (Fluka, Cat. No. 09440). LCMS (M+H)+: m/z=553.2.