Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)SC)[C:4]#[N:5])#[N:2].O.[NH2:20][NH2:21]>CO>[NH2:2][C:1]1[NH:21][N:20]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5]
Reactant: CCOc1ccc(NC(SC)=C(C#N)C#N)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: CCOc1ccc(Nc2n[nH]c(N)c2C#N)cc1

Procedure:
A mixture of 21.5 g (82.9 mmol) of 2-cyano-3-(4-ethoxy-phenylamino)-3-methylmercapto-acrylonitrile, 4.31 ml (87 mmol) of hydrazine hydrate and 110 ml of methanol is heated under reflux for 7 hours and then concentrated by evaporation in vacuo. Recrystallization of the residue from ethyl acetate/hexane yields the title compound; m.p. 166-167° C.
Reaction SMILES: Cl.[CH:2]1([N:5]2[CH2:10][C:9]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[O:8][CH2:7][C:6]2=[O:16])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[CH:38][CH:39]=[N:40]3)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)[C:25]#[N:26]>CN(C)C=O.O>[CH:2]1([N:5]2[CH2:10][C:9]3([CH2:11][CH2:12][N:13]([CH:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:42]=[C:41]6[C:36]([CH:37]=[CH:38][CH:39]=[N:40]6)=[CH:35][CH:34]=5)=[CH:29][CH:28]=4)[C:25]#[N:26])[CH2:14][CH2:15]3)[O:8][CH2:7][C:6]2=[O:16])[CH2:4][CH2:3]1
Reactant: N#CC(Br)c1ccc(-c2ccc3cccnc3c2)cc1
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.101 mmol) in N,N-dimethylformamide (0.5 mL) was treated with potassium carbonate (0.209 mmol) and 2-bromo-2-(4-(quinolin-7-yl)phenyl)acetonitrile (0.070 mmol). The reaction was stirred overnight at room temperature, at which point it was diluted with water (50 mL) and was extracted with three times with dichloromethane. The aqueous layer was further diluted with brine (25 mL) and was extracted twice with tetrahydrofuran. The organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (0-9% methanol/dichloromethane). The fractions containing the desired product were combined, concentrated in vacuo, and lyophilized from water to afford the title compound a pale yellow solid (15%). MS(ES)+ m/e 453.2 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:7]=1[OH:15])([CH3:5])[CH3:4].O>C(O)(=O)C>[Br:1][C:10]1[CH:11]=[C:6]([CH:3]([CH3:5])[CH3:4])[C:7]([OH:15])=[C:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=1
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cc(Br)cc(C(C)C)c1O
Reaction time: 6 h
Yield: 64.9 %

Procedure:
This is a modification of the procedure of Schuster, Ingeborg I.; Parvez, Masood; Freyer, Alan J. J. Org. Chem. 1988, 53, 5819. A solution of bromine (6.3 mL, 119 mmol) in acetic acid (40 mL) was added dropwise to a stirred, room temperature solution of 2,6-diisopropylphenol (20 mL, 97.1 mmol of 90% tech. grade) in acetic acid (280 mL). After 6 h, water was added and the mixture was extracted with ether. The ether phase was dried and concentrated and the residue was flash chromatographed (petroleum ether: eluent) to provide 4-bromo-2,6-diisopropylphenol (16.2 g, 65%) as a red oil. This oil was dissolved in DMF (50 mL), iodomethane (11.7 mL, 189 mmol) and potassium carbonate (26.3 g, 117 mL) were added to it. This reaction mixture was stirred for 5 h and diluted with water. This mixture was extracted with ether and the ether extracts were dried, concentrated and flash chromatographed (petroleum ether: eluent) to provide the title compound as a colorless oil (15.4 g, 90%): NMR (CDCl3); δ 7.17 (s, 2H), 3.70 (s, 3H), 3.29 (septet, 1H), 1.20 (d, 12 H).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:31]=[CH2:32].Br[C:40]1[CH:41]=[C:42]([CH2:61][CH2:62][C:63]([O:65][CH3:66])=[O:64])[C:43]2[CH2:44][CH2:45][CH:46]([NH:50][S:51]([C:54]3[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=3)(=[O:53])=[O:52])[CH2:47][C:48]=2[CH:49]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:60][C:57]1[CH:56]=[CH:55][C:54]([S:51]([NH:50][CH:46]2[CH2:47][C:48]3[C:49]([CH:32]=[CH:31][C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:40][CH:41]=[C:42]([CH2:61][CH2:62][C:63]([O:65][CH3:66])=[O:64])[C:43]=3[CH2:44][CH2:45]2)(=[O:53])=[O:52])=[CH:59][CH:58]=1
Reactant: COC(=O)CCc1cc(Br)cc2c1CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(C=CC(=O)OC(C)(C)C)c2c1CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 110 °C
Reaction time: 8 h

Procedure:
1.25 g (4 mmol) of tri-o-tolylphosphine, 8.5 ml of triethylamine, 230 mg (1 mmol) of palladium acetate and 9 ml of tert-butyl acrylate are added to a solution of 10 g (20.5 nmol) of methyl 3-(3-bromo-6-{[(4-chlorophenyl)sulphonyl]amino}-5,6,7,8-tetrahydro-1-naphthyl)propanoate, described in Application EP 864 561, in 250 ml of DMF. The reaction mixture is stirred at 110° C. for 8 hours. The solvent is then evaporated off, and purification by chromatography on silica gel, using as eluant a cyclohexane/ethyl acetate mixture (80/20), yields the expected product.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]([NH:8][C:9]1[NH:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23]C)=[CH:12][C:13]=1[C:14]([NH2:16])=[O:15])=[O:7].O>ClCCl>[NH2:5][C:6]([NH:8][C:9]1[NH:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])=[CH:12][C:13]=1[C:14]([NH2:16])=[O:15])=[O:7]
Reactant: COc1ccccc1-c1cc(C(N)=O)c(NC(N)=O)[nH]1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: NC(=O)Nc1[nH]c(-c2ccccc2O)cc1C(N)=O
Reaction time: 0.5 h

Procedure:
Boron tribromide in dichloromethane solution (17%, 5.8 mL, 5.8 mmol) was added dropwise to a suspension of 2-aminocarbonylamino-5-(2-methoxyphenyl)pyrrole-3-carboxamide (Compound No. 1-9, 0.40 g, 1.5 mmol) in anhydrous dichloromethane (8 mL) for 7 minutes at −78° C., and the mixture was stirred for 30 minutes. Moreover, the mixture was stirred under ice-cooling for 5 hours, water (25 mL) was added thereto. The precipitated solid was filtered off with chloroform, dried under reduced pressure to give the target compound (0.39 g) quantitatively as a gray solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.CCN(C(C)C)C(C)C.[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:30]=1[S:37](Cl)(=[O:39])=[O:38]>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([NH:18][S:37]([C:30]3[C:31]([CH3:36])=[CH:32][C:33]([CH3:35])=[CH:34][C:29]=3[CH3:28])(=[O:39])=[O:38])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccc3nc(-c4c(Cl)cccc4Cl)[nH]c3c2)c(C)c1
Reaction time: 8 h

Procedure:
To a vial containing a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazol-5-ylamine, prepared as described in Example 1-6, in dioxane (0.2 M, 0.10 mL) was added DIPEA (0.5 M in toluene, 0.050 mL), followed by 2,4,6-trimethyl-benzenesulfonyl chloride (0.2 M in toluene, 0.12 mL). After overnight at ambient temperature, solid phase extraction (SPE) by strong cation exchange (SCX) was followed by silica gel column chromatography to give N-[2-(2,6-Dichloro-phenyl)-3H-benzoimidazol-5-yl]-2,4,6-trimethyl-benzenesulfonamide: MS (m/z) 460.06 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1>C1COCC1.C(Cl)(Cl)Cl>[O:12]=[C:9]1[NH:8][C:7]2[CH:13]=[C:3]([CH:2]=[O:1])[CH:4]=[CH:5][C:6]=2[S:11][CH2:10]1
Reactant: O=C1CSc2ccc(CO)cc2N1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2c(c1)NC(=O)CS2
Temperature: 70 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
To a solution of 6-hydroxymethyl-4H-benzo[1,4]thiazin-3-one (360 mg, 1.8 mmol) in THF/CHCl3 (2:1, 18 mL) was added MO2 (1.6 g, 18 mmol) and the resulting suspension was heated to 70° C. and stirred for 4 h. The suspension was filtered through diatomaceous earth and the filtrate was concentrated. The resulting solid was triturated with EtOAc/hexanes (1:1) and a minimal amount of CH3OH to provide 200 mg (56%) of the title compound as a tan solid. MS (ESI): exact mass calculated for C9H7NO2S, 193.02; m/z found, 194.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.94 (s, 1H), 8.78 (br s, 1H), 7.54-7.49 (m, 2H), 7.37 (d, J=1.5, 1H), 3.52 (s, 2H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:56][C:57]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:58]=1[C:64]1[CH2:68][NH:67][CH:66]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:65]=1>CN(C=O)C>[F:56][C:57]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:58]=1[C:64]1[CH2:68][N:67]([C:13]([C@@H:9]([NH2:8])[CH:10]([CH3:12])[CH3:11])=[O:14])[CH:66]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:65]=1
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@H](N)C(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reaction time: 20 h

Procedure:
N-(tert-butoxycarbonyl)-L-valine (101 mg, 0.464 mmol, 2.00 equiv), PYBOP (243 mg, 0.467 mmol, 2.00 equiv), and triethylamine (0.163 mL, 1.17 mmol, 5.00 equiv) were added to a solution of 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (24, 0.233 mmol, 1 equiv) in DMF (10 mL) at 23° C., and the resulting mixture was stirred for 20 hours. The reaction mixture was partitioned between a 3:1 mixture of saturated aqueous sodium bicarbonate solution and brine (50 mL) and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in a 1:1 mixture of trifluoroacetic acid and dichloromethane (10 mL), and the resulting solution was allowed to stand for 45 minutes, then concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TPA present) to provide (1S)-1-{[4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2-methylpropylamine (15-1) as a 1:1 mixture of diastereomers (tan gum) (isolated as the TFA salt). LRMS m/z (M+H) 357.2 found, 357.2 required.
Reaction SMILES: [CH3:1][N:2]([CH3:45])[C:3](=O)[CH2:4][NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl.ClCCN1C[CH2:54][O:53][CH2:52]C1>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:4][CH2:3][N:2]1[CH2:45][CH2:54][O:53][CH2:52][CH2:1]1)[CH2:23][CH2:22]2
Reactant: ClCCN1CCOCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-(2-chloroethyl)morpholine hydrochloride as the alkylating agent in Step 1. The product was isolated as a white solid (65 mg, 49.4%). LCMS: m/e 643.6 (MH+), 2.35 min (method 13). 1H NMR (400 MHz, MeOD) δ ppm 7.95 (m, J=8.3 Hz, 2H), 7.24 (m, J=8.3 Hz, 2H), 5.31 (d, J=4.8 Hz, 1H), 4.86 (s, 1H), 4.74 (s, 1H), 3.82-3.99 (m, 4H), 3.37-3.58 (m, 4H), 3.21 (d, J=4.5 Hz, 2H), 3.19 (br. s., 2H), 2.67-2.86 (m, 1H), 2.02-2.26 (m, 5H), 1.83-1.90 (m, 1H), 1.64-1.81 (m, 8H), 1.45-1.64 (m, 7H), 1.34-1.45 (m, 2H), 1.27-1.34 (m, 1H), 1.15-1.27 (m, 4H), 1.12 (s, 3H), 1.04 (s, 3H), 0.99 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([N:12]2[CH2:21][C:20]3[CH:19]=[N:18][N:17]([CH3:22])[C:16]=3[NH:15][C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:27][CH2:28][C:29]([N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)=[O:30]>CO.C(O)(=O)C>[OH:37][CH:34]1[CH2:33][CH2:32][N:31]([C:29](=[O:30])[CH2:28][CH2:27][C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:21][C:20]4[CH:19]=[N:18][N:17]([CH3:22])[C:16]=4[NH:15][C:14]4[CH:23]=[CH:24][CH:25]=[CH:26][C:13]3=4)=[O:11])=[CH:9][C:4]=2[CH3:3])[CH2:36][CH2:35]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
Sodium borohydride (4 mg, 0.1 mmol) was added to a solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidin-4-one (Compound number 701) (50 mg, 0.11 mmol) in methanol/acetic acid (99:1, v/v, 100 ml) and the mixture was stirred at room temperature for 1 h. Sodium borohydride (4 mg, 0.11 mmol) was added again and the mixture was stirred for 1 h at room temperature then concentrated in vacuo. The residue was dissolved in di-chloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo to give a white powder identified as the title compound (28 mg, 56%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:21])[C:16]([CH:19]=O)=[CH:17][N:18]=3)[S:13][C:6]=12.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:21])[C:16]([CH2:19][NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: COCCN
Reactant: Cn1c(C=O)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCCNCc1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.6 %

Procedure:
To a suspension of 43 (1.3 g, 3.26 mmol) in dry DCM (50 mL) at RT was added 2-methoxyethanamine (1.226 g, 16.32 mmol), acetic acid (0.98 g, 16.32 mmol) and sodium triacetoxyborohydride (3.46 g, 16.32 mmol), and the reaction mixture was stirred at RT for 24 hours. It was then diluted with additional DCM and washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated to dryness to afford 44 (1.5 g, 100% yield) as an yellow oil which was used crude in the next step with no additional purification. MS (m/z): 458.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[S:4][C:3]=1[C:12](=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(O[N:25]=O)CC(C)C>C(O)(=O)C.O1CCOCC1>[C:14]([C:13]1[N:25]=[N:1][C:2]2[C:10]3[CH:9]=[CH:8][C:7]([CH3:11])=[N:6][C:5]=3[S:4][C:3]=2[C:12]=1[OH:18])([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CC(=O)c1sc2nc(C)ccc2c1N
Reactant: CC(C)CCON=O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1nnc2c(sc3nc(C)ccc32)c1O
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of 6 g (0.022 mol) of 3-amino-2-carbomethoxyacetyl-6-methyl-thieno[2,3-b]pyridine in 1.8 ml acetic acid and 180 ml dioxane was slowly added 4.8 g (4.2 ml, 0.041 mol) of isoamylnitrite and stirring continued for 24 hours. It was then poured on ice-water, filtered and washed with water. The crude product was crystallized from DMSO/H2O to give 4.0 g (64%) of 3-carbomethoxy-4-hydroxy-7-methylpyrido[3',2':4,5]-thieno[3,2-c]pyridazine; m.p., 265°-268° C.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][C:25]([CH3:36])=[N:24][N:23]=2)=[CH:18][CH:17]=1>ClCCl>[C:8]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][C:25]([CH3:36])=[N:24][N:23]=2)=[CH:18][CH:17]=1)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=NN=C(c2ccc(NC(=O)C(C)(C)C)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
1.56 ml (11.2 mmol) of triethylamine and 1.38 ml (11.2 mmol) of pivaloyl chloride were added to a solution of 3 g (10.2 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 160 ml of dichloromethane and the reaction mixture was stirred at 25° C. for one hour. The precipitate formed Was filtered, washed with 3×5 ml of dichloromethane, then with 3×20 ml of water and dried to yield 1.59 g of pure product, m.p. 225°-227° C. (decomp.). The other portion of the product was isolated from the organic phase. The filtrate was extracted with 3×20 ml of water, then with 3×15 ml of 4% aqueous sodium hydroxide solution, finally with 2×30 ml of water. The organic layer was subsequently dried and evaporated under reduced pressure. The crystalline residue was combined with the former product of 1.59 g and suspended in 20 ml of hot ethanol. The product was filtered after cooling, washed with 3×3 ml of ethanol and dried to yield 3.38 g (87.8%) of the pure product, m.p.: 225°-227° C. (decomp.).
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]2[CH3:30])=[CH:9][C:8]=1[CH3:31])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:29][C:24]1[CH:23]=[C:22]([C:16]2([C:18]([F:20])([F:19])[F:21])[O:15][N:14]([CH3:30])[CH:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:32])=[O:5])=[C:8]([CH3:31])[CH:9]=3)[CH2:17]2)[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: Cc1cc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-isoxazolidin-3-yl]-2-methyl-benzoic acid tert-butyl ester (Example I4) (0.67 g) in dichloromethane (15 ml) was added trifluoroacetic acid (“TFA”) (1.05 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The dichloromethane was evaporated and ethyl acetate was added. The mixture was washed with water, dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to give 4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-isoxazolidin-3-yl]-2-methyl-benzoic acid as a mixture of diastereoisomers (0.56 g). 1H-NMR (CDCl3, 400 MHz): 8.05 (m, 1H), 7.45-7.15 (m, 5H), 3.90-3.60 (m, 1H), 3.35-2.60 (m, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[Br:13][CH2:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1ccc2c(c1)CCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: O=C(CBr)c1ccc2c(c1)CCC2
Reaction time: 23 h
Yield: 94.2 %

Procedure:
To a solution of 5-acetylindan (500 mg, 3.1 mmol) in dichloromethane-methanol (2:1, 15 ml) was added tetrabutylammonium tribromide (1.64 g, 3.4 mmol) was added at room temperature. After 23 h, the mixture was concentrated and the residue was partitioned between diethyl ether (50 ml) and water (50 ml). The organic layer was separated and washed with water (50 ml), brine (50 ml), and dried (MgSO4). Removal of solvent gave 698 mg (56%) of the title compound as white solids.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccccn1
Product: c1ccc(CN2CCC(Nc3ccccn3)CC2)cc1

Procedure:
Prepared from 2-bromopyridine and 1-benzyl-4-aminopiperidine using Method A-B.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH2:21]([O:24][C:25]([C:27]1[O:28][C:29]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:30]=2[N:31]=1)=[O:26])[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O>[CH2:21]([O:24][C:25]([C:27]1[O:28][C:29]2[CH:35]=[CH:34][C:33]([O:36][CH2:2][C:3]3[CH:20]=[CH:19][CH:18]=[C:5]([O:6][CH2:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:4]=3)=[CH:32][C:30]=2[N:31]=1)=[O:26])[CH2:22][CH3:23]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CCCOC(=O)c1nc2cc(O)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1nc2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2o1

Procedure:
A mixture of 3.47 g of 2-((3-chloromethylphenoxy)methyl)quinoline, 2.7 g of n-propyl-5-hydroxybenzoxazole-2carboxylate, 1.69 g of potassium carbonate and 1 ml of dimethylformamide is refluxed in 50 ml of acetone for 41 hours. The mixture is concentrated in vacuo and the residue is dissolved in water. This solution is neutralized with diluted hydrochloric acid and the resulting solid is filtered off and purified by flash silica gel chromatography in propanol-dimethylformamide to give n-propyl-5-(3-(quinolin-2-ylmethyloxy)benzyloxy)-benzoxazole-2-carboxylate
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([N:18]2[CH2:23][C:22](=[O:24])[NH:21][C:20](=[O:25])[CH2:19]2)[CH:3]=1.[NH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([N:18]3[CH2:23][C:22](=[O:24])[NH:21][C:20](=[O:25])[CH2:19]3)[CH:3]=[C:2]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(N2CC(=O)NC(=O)C2)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(=O)NC(=O)C2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
119 mg of (S)-4-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}piperazine-2,6-dione, 34 mg of 2-aminopyrazine, 19 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 139 mg of tripotassium phosphate and 17 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added to 2.5 ml of degassed 1,4-dioxane, and then the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 26 mg of the objective compound as pale yellow powder.