Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[CH3:9][C:10]([CH:12]=O)=O.C(OCC)(=O)C>CO>[CH3:12][C:10]1[N:8]=[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][C:4]2=[N:7][CH:9]=1
Reactant: Nc1ccncc1N
Reactant: CC(=O)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cnc2ccncc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
Pyridine-3,4-diamine (2.00 g, 18.3 mmol) was dissolved in methanol (100 mL) and cooled in an ice bath. Pyruvic aldehyde (40% wt., 3.36 mL, 22.0 mmol) was added, dropwise, and the solution was allowed to warm to ambient temperature where it was stirred, under nitrogen, for 18 h. The reaction was monitored by LC-MS and pyruvic aldehyde (2.5 mL, 16.4 mmol) was added and the solution stirred at room temperature, under nitrogen for an additional 5 h. The solvent was removed, in vacuo, to give a black liquid which solidified to a black solid (3.58 g) upon standing. This material was adsorbed onto silica gel and purified by column chromatography, eluting with a solution of 1:1 hexane:ethyl acetate to give a brown solid (2.18 g, 82% Yield). 1H NMR 400 MHz (DMSO): δ=9.43 (s, 1H), 9.00 (s, 1H), 8.81 (d, 1H, J=5.9 Hz), 7.91 (dd, 1H, J=5.7 Hz, J=0.8 Hz), 2.79 (s, 3H). HPLC (Column; Xterra RP18, 3.5 μm, 4.6×150 mm, Column temp.=40° C.), Flow=1.2 mL/min., 85/15-5/95, 10 min., 5/95, 5.0 min., (25 mM HCO2NH4 buffer, pH=3.5/AcN/MeOH), No impurities @ 210-370 nM, and no impurities @ 306 nM, retention time =3.5 min. Calculated mass=145.06, [M+H]+=146.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH:24]1[O:26][CH2:25]1>CO>[CH2:1]([N:8]([CH2:25][CH:24]([OH:26])[C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[Cl:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CCNCc2ccccc2)cc1OC
Reactant: Clc1ccccc1C1CO1
Solvent: CO
Product: COc1ccc(CCN(Cc2ccccc2)CC(O)c2ccccc2Cl)cc1OC

Procedure:
Similarly 2.71 g. (0.01 mol) of N-benzyl-3,4-dimethoxyphenethylamine and 2.33 g. (0.015 mol) of o-chlorostyrene oxide are reacted in methanol to give N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-chlorophenyl)ethylamine. The latter is converted to its hydrochloride, which is dissolved in 90 ml. of methanol and hydrogenated over 1 g. of 10% palladium-on-carbon in 10 ml. of ethyl acetate at room temperature for six hours. The reaction mixture is filtered and evaporated in vacuo to leave N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-chlorophenyl)ethylamine hydrochloride, m.p. 128°-132° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([F:13])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=O)C.C(=O)(O)O.[NH2:19][C:20]([NH2:22])=[NH:21].Cl>C(O)C.O>[NH2:21][C:20]1[NH:22][C:4](=[O:3])[C:5]([F:13])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:19]=1
Reactant: CCOC(=O)C(F)C(=O)c1ccco1
Reactant: N=C(N)N
Agent: Cl
Agent: O=C(O)O
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2ccco2)c(F)c(=O)[nH]1
Temperature: 100 °C
Yield: 71.8 %

Procedure:
Following the method of Skulnick and Wierenga (Patent WO 86/04583), a mixture of 8.72 g (43.6 mmol) (RS)-2-fluoro-3-furan-2-yl-3-oxo-propionic acid ethyl ester and 8.89 g (49.3 mmol) guanidine carbonate in 30 ml ethanol was heated at 100° C. for 16 hours. The reaction mixture was then cooled to 0° C. and diluted with 100 ml water. 1M hydrochloric acid was added dropwise until the mixture was ca pH 3, whereupon the resulting crystals were collected by filtration and washed sequentially with water and with ether to afford 6.11 g (72%) 2-amino-5-fluoro-6-furan-2-yl-3H-pyrimidin-4-one as a brown crystalline solid. EI-MS m/e (%): 95 (M+, 100), 154 ([M—MeCN]+, 24).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]([N:49]1[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][CH2:57]O)[CH2:51][CH2:50]1)(=[O:48])[CH3:47]>>[C:46]([N:49]1[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][CH2:57][O:26][C:20]2[CH:19]=[C:18]3[C:23]([C:14]([Cl:13])=[N:15][CH:16]=[N:17]3)=[CH:22][C:21]=2[O:24][CH3:25])[CH2:51][CH2:50]1)(=[O:48])[CH3:47]
Reactant: CC(=O)N1CCN(CCCO)CC1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Diethyl azodicarboxylate (0.243 g, 1.396 mmol) was added dropwise to a solution of 4-chloro-7-hydroxy-6-methoxyquinazoline (0.245 g, 1.16 mmol), triphenylphosphine (0.396 g, 1.51 mmol) and 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.238 g, 1.28 mmol), (prepared as described for the starting material in Example 1 or Example 7). After stirring at ambient temperature for 1 hour, the mixture was poured onto silica and eluted with increasingly polar mixtures of methylene chloride and methanol to give 7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-chloro-6-methoxyquinazoline (0.29 g, 66%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Br-].C(OCC[N+]1C(C)=C(CCO)SC=1)C.[CH2:30]([C@H:34]1[CH2:39][CH2:38][C@H:37]([CH2:40][CH2:41][CH:42]=[O:43])[CH2:36][CH2:35]1)[CH2:31][CH2:32][CH3:33]>O1CCOCC1>[CH2:30]([C@H:34]1[CH2:35][CH2:36][C@H:37]([CH2:40][CH2:41][C:42](=[O:43])[CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:38][CH2:39]1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[C@H]1CC[C@H](CCC=O)CC1
Reactant: C=CC(=O)OCC
Agent: CCOCC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCC[C@H]1CC[C@H](CCC(=O)CCC(=O)OCC)CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
7.5 g of ethyl acrylate are dissolved in 100 ml of dry dioxan under nitrogen gasification, treated with 6.1 g of triethylamine and 1.4 g of 3-(2-ethoxyethyl)-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium bromide and heated to 80° C. A solution of 19.6 g of 3-(trans-4-butylcyclohexyl)propanal and 7.5 g of ethyl acrylate in 50 ml of dioxan is added dropwise within 5 hours. The mixture is stirred at 80° C. for a further 15 hours, then cooled to room temperature and freed from solvent on a rotary evaporator. The residue is taken up in 200 ml of tert.butyl methyl ether and washed successively with dilute sulphuric acid, dilute sodium hydrogen carbonate solution and water. The aqueous phases are back-extracted with 100 ml of tert.butyl methyl ether. The combined organic phases are dried over sodium sulphate and freed from solvent on a rotary evaporator. The crude product of ethyl 6-(trans-4-butylcyclohexyl)-4-oxo-caproate obtained is recrystallized from ethyl acetate.
Reaction SMILES: Cl.[O:2]([CH2:9][CH2:10][NH2:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C2C=CC=CC=2)[C@@H:24]([CH2:35][O:36]C(=O)C2C=CC=CC=2)[O:23][C@H:22]1[N:45]1[CH:53]=[N:52][C:51]2[C:46]1=[N:47][C:48]([Cl:55])=[N:49][C:50]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C.N>O1CCOCC1>[Cl:55][C:48]1[N:49]=[C:50]([NH:11][CH2:10][CH2:9][O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:51]2[N:52]=[CH:53][N:45]([C:46]=2[N:47]=1)[C@@H:22]1[O:23][C@H:24]([CH2:35][OH:36])[C@@H:25]([OH:26])[C@H:21]1[OH:20]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NCCOc1ccccc1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCOc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared by reacting 2-phenoxyethylamine hydrochloride (0.80 g, 4.6 mmol) with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.0 g, 3.2 mmol) in dioxan (25 ml) in the presence of triethylamine (1.0 g, 9.6 mmol) followed by deprotection of the purified product using methanolic ammonia to provide the title nucleoside (0.75 g, 60%)(following flash chromatography) as an amorphous foam, 1H NMR (DMSO-d6)δ 3.52-3.59 (1H, m, H-5'a), 3.64-3.71 (1H, m, H-5'b), 3.82 (2H, q, --OH2 --), 3.96 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.52 (1H, q, H-2'), 5.12 (1H, t, 5'-0H), 5.25, 5.54 (2H, 2d, 2'- and 3'-OH), 5.85 (1H, d, H-1'), 6.92-7.02 (3H, m, Ar--H), 7.26-7.34 (2H, t, Ar--H), 8.46 (1H, m, H-8), 8.56 (1H, br, t, N--H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=[C:9]([C:11]#[N:12])[N:10]=1)=[O:5])C.[OH-:21].[Na+].[OH-].[K+].Cl>CCO.O>[C:11]([C:9]1[N:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=1)(=[O:21])[NH2:12]
Reactant: [OH-]
Reactant: CCOC(=O)c1nc(C#N)cn1COCC[Si](C)(C)C
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(C(N)=O)nc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid ethyl ester (prepared in Example 11, step (c))(2.0 g, 6.8 mmol) in 15 mL of EtOH was added 5 N NaOH (2.0 mL, 10 mmol) and the reaction stirred for 8 h at RT. The mixture was concentrated, then water (20 mL) and 2 N KOH (3.4 mL, 6.8 mmol) was added and the mixture heated to 90° C. for 1 h. The mixture was cooled in an ice bath and the pH adjusted to 4 with 3 N HCl and a white ppt collected by filtration and dried under vacuum to give 1.5 g (77%) of the title compound. Mass spectrum (ESI, m/z): Calcd. for C1, H19N3O4Si, 286.1 (M+H), found 285.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23](O)=[O:24])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[Cl:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1>C1COCC1>[Cl:53][C:54]1[CH:60]=[CH:59][C:57]([NH:58][C:23]([C:15]2[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:13][C:12]=3[CH:14]=2)=[O:24])=[CH:56][CH:55]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4ccccc4Cl)[nH]c23)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(Cl)cc3)cc3nc(Nc4ccccc4Cl)[nH]c23)O1
Yield: 23.1 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(2-chlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-12, 0.050 g, 0.139 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.089 g, 0.277 mmol), TEA (1.0 mL), DMF (1.0 mL), THF (5.0 mL) and 4-chloro aniline (0.035 g, 0275 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.60 (s, 6H), 3.17 (s, 2H), 7.05 (t, J=7.5 Hz, 1H), 7.36-7.43 (m, 2H), 7.49 (d, J=7.8 Hz, 2H), 7.75 (d, J=8.1 Hz, 2H), 8.58-8.60 (m, 1H), 9.07 (s, 1H), 9.87 (s, 1H), 11.02 (s, 1H), 11.36 (s, 1H); MS [M+H]+: 467.23.
Reaction SMILES: Cl.F[C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[CH3:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:14]([F:13])([F:23])[F:24])=[CH:17][CH:18]=1
Reactant: Cc1cccc([N+](=O)[O-])c1F
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc([N+](=O)[O-])c1Nc1ccc(OC(F)(F)F)cc1

Procedure:
The product (1.92 g) is obtained as a hydrochloride according to the method of stage 1 of Example 4, by using 1 g of 2-fluoro-3-methyl-nitrobenzene and 1.3 mL of 4-trifluoromethoxy-aniline in the presence of 1.16 g of potassium tert-butanolate in 10 mL of DMSO.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][N:10]([CH3:21])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[N:12][N:13]=1.Cl[C:23]1C=CC=CC=1C(NNC(=O)C1C=CC(C)=CC=1)=O>>[CH3:23][C:6]1[CH:5]=[CH:4][C:3]([C:8]2[NH:9][N:10]([CH3:21])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:12][N:13]=2)=[CH:2][CH:7]=1
Reactant: CN1NC(c2ccccc2Cl)=NN=C1c1ccccc1Cl
Reactant: Cc1ccc(C(=O)NNC(=O)c2ccccc2Cl)cc1
Product: Cc1ccc(C2=NN=C(c3ccccc3Cl)N(C)N2)cc1

Procedure:
By the method of Example 1 stages (b) and (c), the above compound was prepared from the product of stage (a) of this Example. Mp 152°-154° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1COCC1>[CH:32]1([NH:38][C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCCCC1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC2CCCCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 18 h

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) and cyclohexylamine (100 mg, 1 mmol) were combined in THF (10 mL) and stirred under Ar at 23° for 18 h. The solvents were removed in vacuo, and the residue was flash chromatographed with 50-100% CH2Cl2/hexane. Recrystallization from CH2Cl2/hexane gave the title compound as a white-crystalline solid. mp 218-219° C., LC MS m/z=465 (MH+) Retention time=2.8 min.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][NH2:38])=[CH:6][CH:5]=1.[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH2:48][S:49](Cl)(=[O:51])=[O:50])=[CH:44][CH:43]=1)#[N:41]>>[CH:23]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13]([CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:39])=[CH:5][CH:6]=2)=[C:14]1[CH2:36][CH2:37][NH:38][S:49]([CH2:48][C:45]1[CH:46]=[CH:47][C:42]([C:40]#[N:41])=[CH:43][CH:44]=1)(=[O:51])=[O:50])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: N#Cc1ccc(CS(=O)(=O)Cl)cc1
Product: N#Cc1ccc(CS(=O)(=O)NCCc2c(CCOc3ccc(C(=O)O)cc3)c3cc(Cl)ccc3n2C(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (Step 6, Example 1)and (4-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH:14][NH:15][C:16]([O:18]C(C)(C)C)=O)[CH3:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl>[C:16]([NH:15][NH:14][C@@H:12]([C:9]1[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=1)[CH3:13])(=[O:18])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1ccc(C(C)NNC(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc([C@@H](C)NNC(=O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Thus the slow moving enantiomer tert-butyl 2-{1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinecarboxylate (0.74 g, 2.42 mmol) from a chiral separation as described above was treated with TFA/CH2Cl2 (1:1, 10 mL) for 1 h at r.t. The reaction was concentrated on a rotovap and the residual TFA was removed by co-evaporation from toluene. The resulting ethyl 4-(1-hydrazinoethyl)benzoate was then dissolved in CH2Cl2 (15 mL) and cooled to −78° C. A solution of benzoyl chloride (365 μL, 3.15 mmol) and 2,6-di-tert-butyl-4-methylpyridine (745 mg, 3.63 mmol) in CH2Cl2 (5 mL) was added slowly at −78° C. After 3 h at −78° C., the reaction mixture was loaded quickly on a SiO2 column and eluted with 30% EtOAc/hexane. Fractions containing product were concentrated and purified further on HPLC using Kromasil C8 column (10% to 70% CH3CN/H2O/0.1% TFA, 12 min), and again on silica gel column (30% EtOAc/Hexane) to give (R)-(+)-ethyl 4-[1-(2-benzoylhydrazino)ethyl]benzoate. HPLC/MS: m/z=313.3 (M+1)+, Rt=3.08 min. Daicel column Chiralcel OJ, 40° C., 0.5 mL/min, 10% isopropanol/90% n-heptane: t 35.79 min; [α]D20=+192.40 (c1, CHCl3); 1H NMR (500 MHz, CDCl3): δ 8.03 (2H, d, J=8.0 Hz), 7.94 (1H, br s), 7.66 (2H, d, J=7.5 Hz), 7.51 (1H, t, J=7.5 Hz), 7.54 (2H, d, J=8.0 Hz), 7.40 (2H, t, J=8.0 Hz), 4.39 (2H, q, J=7.0 Hz), 4.36 (1H, q, J=7.0 Hz), 1.46 (3H, d, J=6.0 Hz), 1.41 (3H, t, J=7.0 Hz); 13C NMR (500 MHz, CDCl3): δ 167.76, 166.69, 148.16, 132.70, 132.27, 130.21, 130.18, 128.94, 127.47, 127.15, 61.22, 60.21, 21.21, 14.58. (S)-(−)-ethyl 4-[1-(2-benzoylhydrazino)ethyl]-benzoate was similarly prepared from the faster moving isomer of tert-butyl 2-{1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinecarboxylate. HPLC/MS: m/z=313.4 (M+1)+, Rt=3.09 min. Daicel column Chiralcel OJ, 40° C., 0.5 mL/min, 10% isopropanol/90% n-heptane: t 34.99 min; [α]D20=−194.4° (c1, CHCl3); 1H NMR (500 MHz, CDCl3): δ 8.02 (2H, d, J=8.0 Hz), 7.73 (1H, br s), 7.65 (2H, d, J=8.0 Hz), 7.49 (1H, t, J=8.0 Hz), 7.48 (2H, d, J=8.0 Hz), 7.39 (2H, t, J=8.0 Hz), 4.38 (2H, q, J=7.0 Hz), 4.34 (1H, q, J=7.0 Hz), 1.44 (3H, d, J=6.5 Hz), 1.41 (3H, t, J=7.0 Hz); 13C NMR (500 MHz, CDCl3): δ 167.81, 166.74, 148.73, 132.92, 132.15, 130.13, 130.02, 128.90, 127.43, 127.12, 61.20, 60.09, 21.52, 14.58.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][C:19]1=O.Cl>C(OCC)C.CCCCCC>[CH3:17][C:18]1[CH2:22][CH:21]=[C:20]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[CH:19]=1
Reactant: CC1CCCC1=O
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=CC(c2ccc(C(C)(C)C)cc2)=CC1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
1-Bromo-4-t-butylbenzene (18 mL, 104 mmol) was dissolved in diethyl ether (100 mL) and added dropwise at −30° C. with a solution (66 mL, 104 mmol, 1.57 N) of n-butyllithium in hexane. The resultant solution was warmed to room temperature, stirred night and day and added dropwise at −20° C. to a solution of 3-methyl-2-cyclopentanone (10 g, 104 mmol) in diethyl ether (10 mL). Immediately after dropwise addition, the solution was warmed to room temperature and stirred for 3 hours. After termination of the reaction, the reaction solution was added with dilute hydrochloric acid and subjected to layer separation. The organic layer was dried with magnesium sulfate and then had the solvent distilled off under reduced pressure. The crude product was distilled under reduced pressure (105 to 115° C./0.16 mmHg) to obtain 1-methyl-3-(4-t-butylphenyl)-cyclopentadiene (15.3 g, yield: 69%).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH3:9].C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C1COCC1.[Cu](I)I>[CH3:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17]
Reactant: Cc1cnccc1Br
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cnccc1C#C[Si](C)(C)C
Temperature: 50 °C
Yield: 86.9 %

Procedure:
To a solution of 4-bromo-3-methyl pyridine hydrochloride (5.0 g, 24.0 mmol) in THF (degassed, 80 mL) was added copper iodide (450 mg, 2.40 mmol) and triethylamine (20.0 mL, 143.9 mmol). After degassing for 15 min, palladium tetrakis triphenylphosphine (830 mg, 0.72 mmol) and trimethylsilylacetylene (6.10 mL, 43.16 mmol) were added. The mixture was heated at 50° C. for 16 h then cooled to rt and filtered. The crude residue was purified via silica gel chromatography (EtOAc-Hexanes, 10%) to afford the title compound (3.95 g, 87%) as clear but dark oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=1)=O.[OH-].[NH4+]>C(O)C>[C:17]([C:13]1[CH:12]=[C:11]([C:9]2[N:1]=[C:2]3[N:6]([CH:8]=2)[CH:5]=[CH:4][S:3]3)[CH:16]=[CH:15][CH:14]=1)#[N:18]
Reactant: Nc1nccs1
Reactant: N#Cc1cccc(C(=O)CBr)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cccc(-c2cn3ccsc3n2)c1
Reaction time: 20 h
Yield: 81 %

Procedure:
To a mixture of 2-aminothiazole (3.29 g, 32.9 mmol) and 2-bromo-3′-cyano-acetophenone (7.37 g, 32.9 mmol) was added absolute ethanol (250 mL). The reaction was allowed to reflux with vigorous stirring for 20 hours. The reaction mixture was reduced to half its original volume in vacuo. The remaining suspension was poured onto ice-water (200 mL) and the resulting mixture was basified by addition of ammonium hydroxide solution (30%, 100 mL). Product was collected by filtration and washed with water (50 mL), dried in a vacuum oven at 50° C. to provide 6-(3-cyanophenyl)-imidazo[2,1-b]thiazole (6.0 g, 81%). It was used with out further purification. LCMS: 226 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)=[N:7][O:8][C:4]=2[C:3]=1[C:22]([OH:24])=O.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:36]=[N:37][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[N:39][CH:40]=1>CN(C=O)C>[C:42]([NH:41][C:38]1[N:39]=[CH:40][C:35]([NH:34][C:22]([C:3]2[C:4]3[O:8][N:7]=[C:6]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=4)[C:5]=3[CH:20]=[CH:21][C:2]=2[Cl:1])=[O:24])=[CH:36][N:37]=1)(=[O:44])[CH3:43]
Reactant: O=C(O)c1c(Cl)ccc2c(Nc3cccc(C(F)(F)F)c3)noc12
Reactant: CC(=O)Nc1ncc(N)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ncc(NC(=O)c2c(Cl)ccc3c(Nc4cccc(C(F)(F)F)c4)noc23)cn1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A round-bottomed flask was charged with 6-chloro-3-(3-(trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxylic acid (0.1 g, 0.28 mmol, made by the method described in Example 1), n,n-diisopropylethylamine (0.07 mL, 0.42 mmol), o-(7-azabenzotriazol-1-yl)-n,n,n′,n-tetramethyluronium hexafluorophosphate (0.15 g, 0.39 mmol), and DMF (1 mL). This mixture was stirred for 15 min before N-(5-aminopyrimidin-2-yl)acetamide (0.045 g, 0.29 mmol, Step B) was introduced. The reaction mixture was stirred at 60° C. for 16 h, then partitioned between EtOAc (15 ml) and brine (10 mL). The aqueous layer was back exacted with EtOAc (3×10 mL) and the combined EtOAc layer was dried (Na2SO4) and concentrated. The crude product was dissolved in DCM and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 4% of MeOH in CH2Cl2, to provide N-(2-acetamidopyrimidin-5-yl)-6-chloro-3-(3-(trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxamide as an off-white solid. MS (ESI, pos. ion) m/z: 491 (M+1).
Reaction SMILES: O1CCCC1.[Cl-].[Al+3].[Cl-].[Cl-].[C:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[C:22](=[O:23])[CH2:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[S:18][C:17]=2[CH:28]=1)#[N:11].[N-:29]=[N+:30]=[N-:31].[Na+]>O>[NH:29]1[C:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]3[C:22](=[O:23])[CH2:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18][C:17]=3[CH:28]=2)=[N:11][N:31]=[N:30]1
Reactant: N#CCc1ccc2c(c1)Sc1ccccc1CC2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1Cc2ccccc2Sc2cc(Cc3nnn[nH]3)ccc21

Procedure:
Add to 25 cc. of tetrahydrofuran cooled in an ice bath 1.59 gm. (11.9 mmole) of aluminum chloride, 1.33 gm. (5.25 mmole) of 3-cyanomethyl-10,11-dihydro-11-oxodibenzo[b,f]thiepin and 1.55 gm. (23.8 mmole) of sodium azide. Reflux the mixture for 19 hours, cool, dilute with water and acidify. Extract the mixture into ethyl acetate and evaporate. Triturate the residue in ether and separate the title product by filtration.