Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[I:19][CH2:20]I>C1COCC1>[I:19][CH2:20][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: COC(=O)C1CCOCC1
Reactant: ICI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(CI)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a stirred solution of methyl tetrahydropyran-4-carboxylate (3.00 g) in anhydrous THF (50 ml) under nitrogen at 0° C. was added a solution of lithium di-isopropylamide (2.0 M, 10.9 ml). After 30 minutes, diiodomethane (8.36 g) was added and the mixture was allowed to warm up to RT and then stirred for 1 h. The mixture was poured onto water (50 ml) and extracted with ether (3×40 ml). The combined ether layers were washed with water (2×20 ml), aqueous hydrochloric acid (2 M, 20 ml), water (20 ml) and brine (20 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified on silica gel, eluting with 3:1 hexane/ether, to give the title compound (3.11 g) as a colourless oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[N:7][C:6]=1[Br:12])C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.O>CCOCC>[Br:12][C:6]1[C:5]([CH2:4][OH:3])=[CH:10][C:9]([CH3:11])=[CH:8][N:7]=1
Reactant: CCOC(=O)c1cc(C)cnc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc(Br)c(CO)c1
Reaction time: 1 h

Procedure:
A solution of 2-bromo-5-methyl-nicotinic acid ethyl ester (0.4 g, 1.63 mmol) (synthesized according to Ponticello's procedure J. Org. Chem., 1978, 43, 2529-2535) in Et2O (10 mL) was dropwise added LiAlH4 (1.0 M in THF, 1.79 mL, 1.79 mmol) at −78° C. After the addition was completed, the suspension was stirred at −78 C for 1 h. EtOAc was carefully added at −78° C. and then water was dropwise added. The organic portion was brought to the usual work-up to give the product without further purification. 1H NMR (300 MHz, CDCl3) 8.13 (s, 1H), 7.68 (s, 1H), 4.73 (s, 2H), 2.33 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].CN(C)C=O.I[CH2:22][CH2:23][CH2:24][CH:25]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH:25]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH2:24][CH2:23][CH2:22][N:8]2[CH2:7][CH2:6][N:5]([C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:4]([CH2:3][O:2][CH3:1])[CH2:9]2)=[CH:31][CH:30]=1
Reactant: COCC1CNCCN1C(=O)C(F)(F)F
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COCC1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1C(=O)C(F)(F)F
Reaction time: 4 h
Yield: 94 %

Procedure:
To a stirred mixture of 6.05 parts of 2-(methoxymethyl)-1-(trifluoroacetyl)piperazine, 5.25 parts of N,N-diethylethananamine and 36 parts of N,N-dimethylformamide were added 11 parts of 1,1'-(4-iodobutylidene)bis[4-fluorobenzene]. Stirring was continued for 4 hours at 75° C. The reaction mixture was cooled and poured onto 400 parts of water. The product was extracted twice with 140 parts of 1,1'-oxybisethane. The combined extracts were dried, filtered and evaporated, yielding 11.5 parts (94%) of 4-[4,4-bis(4-fluorophenyl)butyl]-2-(methoxymethyl)-1-(trifluoroacetyl)piperazine as a residue (intermediate 60).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=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.CN1CCOCC1.[F:56][C:57]([F:66])([F:65])[C:58]1[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=1>C1COCC1.CN(C=O)C>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[C:15]([C:23]([NH:62][C:61]3[CH:63]=[CH:64][C:58]([C:57]([F:56])([F:65])[F:66])=[CH:59][CH:60]=3)=[O:24])=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)cc3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 14.7 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.100 g, 0.254 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.163 g, 0.509 mmol), N-methyl morpholine (1.0 mL), DMF (1.5 mL), THF (7.0 mL) and 4-trifluoro methyl aniline (0.082 g, 0.509 mmol) to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 1.58 (s, 6H), 3.07 (s, 2H), 7.25 (s, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H), 8.45 (s, 2H), 9.91 (s, 1H), 10.99 (s, 1H), 11.55 (s, 1H); MS [M+H]+: 536.22.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[C:5]([CH3:17])([CH3:16])[CH2:4][CH2:3]1)[NH:13][CH2:12][CH2:11][CH2:10]3.[H-].[Na+].Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>C1COCC1>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([CH2:22][N:13]2[C:14]3[C:9](=[CH:8][C:7]4[C:2]([CH3:18])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:17])([CH3:16])[C:6]=4[CH:15]=3)[CH2:10][CH2:11][CH2:12]2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)CCCN3
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2CCCc3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Temperature: 60 °C
Yield: 40.3 %

Procedure:
To a solution of 6,6,9,9-tetramethyl-1,2,3,4,6,7,8,9-octahydrobenzo[g]quinoline (200 mg, 0.823 mmol) in THF (4 mL) was added NaH (30 mg, 1.2 mmol) in one portion at ambient temperature. To this solution was added methyl 4-(bromomethyl)-benzoate (377 mg, 1.6 mmol) in THF (8 mL). The mixture was then heated at 60° C. for 8 h, cooled to ambient temperature, quenched with aqueous saturated NH4Cl (20 mL), extracted with EtOAc (100 mL), dried (MgSO4), concentrated, and purified by column chromatography (10% ether in hexanes) to afford 4-(6,6,9,9-tetramethyl-3,4,6,7,8,9-hexahydro-2H-benzo[g]quinolin-1-ylmethyl)-benzoic acid methyl ester 130 mg (40%): 1H NMR (400 MHz, CDCl3) δ 7.98(½ ABq, 2H, J=9.0 Hz, ArH), 7.38(½ ABq, 2H, J=9.0 Hz, ArH), 6.91(s, 1H, ArH), 6.3(s, 1H, ArH) 4.45(s, 2H, CH2), 3.90(s, 3H, CH3), 3.2(t, 2H, J=5.4 Hz, ring CH2), 2.79(t, 2H, J=6.4 Hz, ring CH2), 2.02(m, 2H, ring CH2), 1.59(s, 4H, 2CH2), 1.22(s, 6H, 2CH3), 1.06(s, 6H, 2CH3).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18]CC)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[CH:25]([NH2:27])=[NH:26].C[O-].[Na+]>CO>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2[N:26]=[CH:25][NH:27][C:16](=[O:18])[C:11]=2[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=CN
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Temperature: 85 °C
Yield: 64.6 %

Procedure:
A mixture of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (50.0 g, 0.168 mol), formamidine acetate (16.2 g, 0.201 mol), 4.37 M of sodium methoxide in methanol (190 mL) and methanol (200 mL) was heated at 85° C. for 16 hour in a 350 mL sealed reaction vessel. The mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in 1N NaOH (150 mL) and poured over ice. Glacial acetic acid was added to the mixture until the pH of the mixture was 7 and a tan solid precipitated out. The solid was filtered, washed with water and cold ether, and dried on high vacuum to yield the title compound as a tan solid (26.2 g, 61.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:30]#[N:31])=[C:11]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]2[N:13]([C:15]([C:18]3[CH:19]=[N:20][C:21](F)=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:14]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:30]#[N:31])=[C:11]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]2[N:13]([C:15]([C:18]3[CH:19]=[N:20][C:21]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:14]=1
Reactant: C1COCCN1
Reactant: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccc(F)nc3)cnc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccc(N4CCOCC4)nc3)cnc12
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
A mixture of 6-(2,4-dichloro-phenyl)-3-(6-fluoro-pyridin-3-yl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carbonitrile (64 mg, 0.14 mmol) and morpholine (0.06 mL, 0.70 mmol) in DMSO (1 mL) was heated at 180° C. and stirred for 30 min. The reaction mixture was cooled to RT, diluted in AcOEt (20 mL) and washed with water (2×10 ml). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness to yield the crude 6-(2,4-dichloro-phenyl)-8-isobutoxy-3-(6-morpholin-4-yl-pyridin-3-yl)-imidazo[1,2-a]pyridine-7-carbonitrile intermediate (67.8 mg) as a brown solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]#[CH:24])[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH:42]3[CH2:47][CH2:46][CH2:45][N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:43]3)(=[O:41])=[O:40])=[CH:35][CH:34]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.O>[C:11]([O:10][C:9]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]1[N:6]=[CH:7][C:2]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH:42]3[CH2:47][CH2:46][CH2:45][N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:43]3)(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[N:3][C:4]=1[C:23]#[CH:24])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#Cc1nc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (2 g, 5.022 mmol) and tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate (2.324 g, 5.148 mmol) were dissolved in MeCN (40.00 mL)/water (8.000 mL). K3PO4 (2.131 g, 10.04 mmol) was added and the mixture was degassed/flushed via nitrogen cycles (×5). Pd[P(tBu)3]2. (128.3 mg, 0.2511 mmol) was added and the reaction mixture placed under an atmosphere of nitrogen using vacuum/nitrogen cycles (×5). The reaction mixture was stirred at ambient temperature for 1 hour and then poured onto a stirred mixture of ethylacetate and saturated aqueous sodium metabisulphite at 10° C. The mixture was stirred for 5 minutes, shaken well and separated. The organic layer was washed with brine (×1), dried over MgSO4, filtered and the solution passed through a Florisil eluting with Ethylacetate. The filtrate was concentrated in vacuo and the residue purified by column chromatography (ISCO Companion, 330 g column, eluting with 0 to 40% Petroleum/Petroleum Ether, loaded in DCM) to give tert-butyl 3-[4-[5-[bis(tert-butoxycarbonyl)amino]-6-ethynyl-pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate as a beige solid (2.45 g, 76% Yield). H NMR (400.0 MHz, DMSO) δ 9.38 (s, 1H), 8.48 (d, 2H), 8.08 (d, 2H), 5.02 (s, 1H), 4.12-3.88 (m, 1H), 3.76 (br d, 1H), 3.43 (br s, 1H), 2.90-2.78 (m, 2H), 2.09 (br s, 1H), 1.75-1.61 (m, 2H) and 1.38-1.18 (m, 28H) ppm;
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:43][CH:44]1[CH2:51][CH:50]2[N:52]([CH3:53])[CH:46]([CH2:47][CH2:48][CH2:49]2)[CH2:45]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:53][N:52]1[CH:46]2[CH2:47][CH2:48][CH2:49][CH:50]1[CH2:51][CH:44]([NH:43][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:11][C:10]=13)=[O:18])[CH2:45]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3ccc(Cl)s3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccc(Cl)s4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.7 %

Procedure:
A mixture of 2-(5-chlorothiophen-2-yl)benzoxazole-4-carboxylic acid (110 mg, 0.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg, 0.78 mmol), 1-hydroxybenzotriazole (106 mg, 0.78 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (111 mg, 0.48 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.22 mL, 1.56 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (2×50 mL), brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5-chlorothiophene-2-yl)benzoxazole-4-carboxamide (19 mg, 12%) as a light brown solid: 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J=6.3 Hz, 1H), 8.20 (dd, J=7.8, 1.0 Hz, 1H), 7.73 (d, J=4.0 Hz, 1H), 7.65 (dd, J=8.1, 1.0 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.06 (d, J=4.1 Hz, 1H), 4.60-4.54 (m, 1H), 3.20-3.10 (m, 2H), 2.67-2.58 (m, 2H), 2.56 (s, 3H), 2.20-2.00 (m, 3H), 1.60-1.45 (m, 3H), 1.25-1.15 (m, 2H); MS (ESI+) m/z 416 (M+H); HPLC>99% (AUC), tR=13.02 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[N:12][N:11]3[CH:29]=2)=[CH:4][CH:3]=1.[I:30]N1C(=O)CCC1=O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]4)=[N:12][N:11]3[C:29]=2[I:30])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(-c4ccc(F)cc4)cn3n2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(-c4ccc(F)cc4)c(I)n3n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 28.0 g (70.5 mmol) of tert-butyl 4-[2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate in 800 mL of tetrahydrofuran cooled to about 0° C. are added 17.4 g (77.5 mmol) of N-iodosuccinimide. After stirring for 18 hours at room temperature, the solvent is evaporated off under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:25][CH3:26])=[C:13]([C:16]3([C:21](OC)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:14]=2)[C@H:9]([N:27]([CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)[C:28]([O:30][CH3:31])=[O:29])[CH2:8][C@@H:7]1[CH3:47])=[O:5])[CH3:2].B.CSC>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:25][CH3:26])=[C:13]([C:16]3([CH2:21][OH:22])[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:14]=2)[C@H:9]([N:27]([CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[C:35]([C:43]([F:45])([F:44])[F:46])[CH:34]=2)[C:28]([O:30][CH3:31])=[O:29])[CH2:8][C@@H:7]1[CH3:47])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(C3(C(=O)OC)CCCC3)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCOC(=O)N1c2cc(C3(CO)CCCC3)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Yield: 3 %

Procedure:
To a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methoxy-7-(1-methoxycarbonyl-cyclopentyl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 27) (700 mg; 1.04 mmol) in 20 mL anhydrous tetrahydrofuran was added borane-dimethylsulfide complex (1M THF; 2.28 mL) and the reaction was heated to reflux for 3 hours. The reaction was quenched with H2O and extracted with 50 mL of ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated. The residue was chromatographed (25% ethyl acetate-hexane) to afford the title product (20 mg). MS m/z 664 (M+ +18); 1H NMR (CDCl3) δ 1.1 (d, 3H), 3.6 (s, 2H), 3.7 (s, 3H), 3.8 (s, 3H), 6.3 (s, 1H), 7.3 (S, 1H), 7.7 (S, 2H), 7.8 (S, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14](OC)=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of Example 1 (c) in dry tetrahydrofuran (40 ml) at 0° C. was treated with lithium aluminum hydride (0.50 g) and the mixture was stirred at 0° C. for 1.5 hours. The cooled solution was treated dropwise with a solution of 2M sodium hydroxide until a white precipitate had formed. Dichloromethane and anhydrous sodium sulfate were added and the solution was filtered and evaporated to give a pale yellow oil (3.0 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9](C)(C)[C:10]([O:12]CC)=O)=O)[CH:2]=1.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:9][C:10](=[O:12])[N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:24]=2)[CH:2]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(C)(C)C(=O)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CC(c2cccnc2)=NN1c1ccccc1
Yield: 93 %

Procedure:
A mixture of 1.5 g (6.8 mmol) of ethyl α-(3-pyridylcarbonyl)isobutyrate and 0.88 g (12 mmol) of phenyl hydrazine was dissolved in 50 ml of toluene, and the solution was dehydrated and heated under reflux in the presence of p-toluenesulfonic acid monohydrate (catalytic amount) for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/2 (v/v)) to give 1.5 g of the object compound as white crystals (yield 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:10]#[N:11])[C:6]([O:12][CH3:13])=[CH:5][N:4]=1.Cl.NO.C([N:19](CC)CC)C.ClC(OC)=O>O.C(#N)C>[NH2:11][C:10]1[N:9]=[C:7]2[N:8]([C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]2[O:12][CH3:13])[N:19]=1
Reactant: COc1ncc(OC)c(NC#N)n1
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Agent: Cl
Agent: NO
Solvent: O
Solvent: CC#N
Product: COc1cnc(OC)n2nc(N)nc12
Temperature: 45 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a 25 mL three-neck round bottom flask were added 1.11 g (5.55 mmol) of 90 wt % 2,5-dimethoxy-4-cyanoaminopyrimidine (2), 463 mg (6.66 mmol) of hydroxylamine hydrochloride, and 9.8 g of acetonitrile. To this mixture was added 681 mg (6.72 mmol) of triethylamine in one portion. The reaction mixture was heated to a gentle reflux (˜45° C.) for 2 h. The reaction mixture was cooled in an ice water bath to about 5.8° C. at which time an additional 716 mg (7.08 mmol) of triethylamine was added in one portion. To this mixture was added 662 mg (7.01 mmol) of methyl chloroformate in one portion at which time the internal reaction temperature rose from 5.8° C. to 12.1° C. The ice water bath was removed and the mixture was stirred at ambient temperature for 1 h and then at reflux (˜76° C.) for about 3 h. The reaction mixture was cooled to ambient temperature and an additional 100 μL of triethylamine was added to adjust the reaction pH to about 7-8. To this mixture was added 11.3 g of water; the mixture was transferred to a 100 mL round bottom flask; and the acetonitrile was removed in vacuo at 60 mm Hg and 30° C. The aqueous slurry was then suction filtered over a medium glass frit and the residue from the flask was transferred with ˜2 g of water. After the cake de-liquored, another 1 g displacement water wash was passed through the cake. After suction air drying the cake for 30 min, the mixture was allowed to dry over a nitrogen pad overnight. This afforded 588 mg (˜97% pure by liquid chromatography (LC) analysis) of 2-amino-5,8-dimethoxy-[1,2,4]-triazolo[1,5-c]pyrimidine (I) as a light yellow solid in 52.8% yield from starting 2,5-dimethoxy-4-cyanoaminopyrimidine (2). 1H NMR (DMSO-d6, 400 MHz) δ 3.90 (s, 3H), 4.06 (s, 3H), 6.28 (br s, 2H), 7.48 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 55.37, 57.04, 123.07, 138.60, 143.73, 148.50, 166.02.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([SH:10])#[N:9].N.S(=O)(O)[O-].[Na+].Cl>>[C:2]1([NH:1][C:8]([NH2:9])=[S:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: N#CS
Agent: Cl
Agent: N
Agent: O=S([O-])O
Product: NC(=S)Nc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
558 Parts of aniline, 479 parts of ammonium rhodanide and 78 parts of a 40% aqueous sodium bisulfite solution are introduced successively into 592 parts of a 37% aqueous hydrochloric acid. This reaction mixture is at first stirred for 8 hours at 80° C., then for 8 hours at 90° C., thereafter cooled to 20° C.; the precipitate formed is filtered off with suction, washed until neutral and dried. 888 Parts (corresponding to 97.4% of the theory) of phenyl thiourea are obtained, which product has a melting point in the range of from 148° to 150° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:22])=[CH:6][CH:5]=1.[H-].[Na+].[CH:26](Br)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:14]=2[CH3:22])=[CH:8][CH:9]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(CCCc2c(C)[nH]c3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCc2c(C)n(C(c3ccccc3)c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product from step 2 (1.66 g, 4.86 mmol) in DMF (20 mL) was added NaH (60% in mineral oil, 0.24 g, 5.83 mmol) under N2 atmosphere. The mixture was stirred for 1 h at room temperature, followed by the dropwise addition of benzhydryl bromide (1.8 g, 7.29 mmol) in DMF (5 mL). This reaction mixture was stirred overnight at room temperature. Water (500 mL) was added to reaction mixture, it was extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated under reduced pressure to a brown syrup, which was purified by silica-gel chromatography using 10% EtOAc/hexanes as eluent to isolate 4-[3-(1-Benzhydryl-2-methyl-1H-indol-3-yl)-propyl]-benzoic acid methyl ester as a white solid in 76% (1.47 g) yield.