Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]([OH:15])[C:10]3([CH2:12][CH2:11]3)[CH2:9]2)[C:5]([F:16])=[C:4]([NH:17][NH2:18])[N:3]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.[CH:40]1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH:19]1([CH2:24][C@@H:25]([C:26]([NH:18][NH:17][C:4]2[C:5]([F:16])=[C:6]([N:8]3[CH2:14][C@@H:13]([OH:15])[C:10]4([CH2:12][CH2:11]4)[CH2:9]3)[N:7]=[C:2]([CH3:40])[N:3]=2)=[O:27])[CH2:29][N:30]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:38]=[O:39])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: NNc1nc(Cl)nc(N2CC(O)C3(CC3)C2)c1F
Reactant: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2C[C@@H](O)C3(CC3)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
5-(2-Chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-5-azaspiro[2.4]heptan-7-ol (167 mg 0.610 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (217 mg, 0.508 mmol), and HOAt (83 mg, 0.610 mmol) were dissolved in 5 mL of DMF. NMM (0.167 mL, 1.525 mmol) was added, followed by EDC (117 mg, 0.6101 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(7S)-7-hydroxy-5-azaspiro[2.4]hept-5-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (223 mg, 79%). LCMS: (M+H)+: 555.3.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2cccc(C(F)(F)F)c2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.42 mmol) and triethylamine (88 μL, 0.63 mmol) in methylene chloride (15 mL) was added dropwise 3-(trifiuoromethyl)benzoyl chloride (93 mg, 0.44 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 130 mg (71%) of the title compound as a viscous oil: [α]21D -25° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 417 (25, M+).
Reaction SMILES: [C:1]1([S:7][C:8]2[C:9]([NH:24][C:25]3[S:29][N:28]=[C:27]([CH:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[N:26]=3)=[N:10][CH:11]=[C:12]([S:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[ClH:45]>O1CCOCC1>[ClH:45].[ClH:45].[C:1]1([S:7][C:8]2[C:9]([NH:24][C:25]3[S:29][N:28]=[C:27]([CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:26]=3)=[N:10][CH:11]=[C:12]([S:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccnc5ccsc45)cc3Sc3ccccc3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1ccc(Sc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Tert-butyl 4-(5-(3-(phenylthio)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate was dissolved in 1:1CH2Cl2:methanol (4 mL) and 4N HCl in dioxane added (2 mL) and stirred at ambient temperature for 1 hour. The solvent was removed and placed on high vacuum to afford the title compound (100 mg, 89.6% yield) as a yellow solid. 1H NMR (d6-DMSO)S 8.70 (m, 2H), 8.20 (m, 3H), 7.95 (m, 1H), 7.40 (m, 5H), 3.80-3.05 (m, 9H). Mass spectrum (apci) m/z=535.2 (M+H-3HCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]2[C:15]([CH3:27])([CH3:26])[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:18]=2)[CH:4]=1.[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:45])=[C:40]([CH:44]=1)[C:41](O)=[O:42])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:45])=[C:40]([C:41]([N:22]2[CH2:23][CH2:24][CH:19]([N:17]3[C:16](=[O:25])[C:15]([CH3:27])([CH3:26])[C:14]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:11]5[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=5[CH:6]=4)=[N:18]3)[CH2:20][CH2:21]2)=[O:42])[CH:44]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc2c1OC(C)(C)C2
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Product: COc1cc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)cc2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B12) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][CH2:24][CH3:25])[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH2:26](OC1N=C(C(O)=O)C=NC=1N1CCCC1)CCC.N[C@@H](CC(C)C)CO>>[OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CCCCOc1nc(C(=O)O)cnc1N1CCCC1
Reactant: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Agent: CC(C)C[C@H](N)CO
Product: CCCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-butoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid and (S)-2-amino-4-methyl-pentan-1-ol (commercially available). m/z (ES+): 365.5 (M+H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([CH3:28])[CH:25]([CH3:27])[CH3:26])[CH:18]=2)[N:9]=1.[CH3:29][C:30]([CH3:32])=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:28][CH:24]([NH:23][C:19]1[CH:18]=[C:17]([C:10]2[N:9]=[C:8]([N:2]3[CH2:3][C@@H:4]4[CH2:7][C@H:1]3[CH2:6][N:5]4[CH:30]([CH3:32])[CH3:29])[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH:11]=2)[CH:22]=[CH:21][N:20]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)=O
Reactant: CC(C)C(C)Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)C(C)Nc1cc(-c2cc3nccn3c(N3C[C@@H]4C[C@H]3CN4C(C)C)n2)ccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of 25 mg (0.066 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl-)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1,2-dimethyl-propyl)-amine in 5 mL chloroform was treated with 38 mg (0.66 mmol) acetone, 41 mg (0.66 mmol) NaBH3(CN) and 1 mL methanol. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, obtained the title compound as a yellow solid. MS (ES+): 420 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:18](=[O:20])[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:12](=[O:22])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=CC([N+]([O-])=O)=CC=1[N+]([O-])=O.CC1(C)[O:47][C@@H:46]([CH2:48][O:49]N)[CH2:45][O:44]1>CC(N(C)C)=O>[OH:47][C@H:46]([CH2:48][OH:49])[CH2:45][O:44][N:17]1[C:18](=[O:20])[C:19]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:11][C:12](=[O:22])[N:13]([CH3:21])[C:14]=2[N:15]=[CH:16]1
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc21
Reactant: CC1(C)OC[C@H](CON)O1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(OC[C@H](O)CO)cnc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 13.2 %

Procedure:
Compound 5F (1.31 g, 3.17 mmol), potassium carbonate (1.1 g, 7.92 mmol) and 1-chloro-2,4-dinitrobenzene (1.60 g, 7.92 mmol) were stirred in DMA at 80° C. for 2 hours. (R)-O-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (4.66 g, 31.7 mmol) was added at r.t and the reaction was stirred for 1 hour at 80° C. Purification by prep-HPLC gave 210 mg (13%) of the title compound as a clear yellow solid (Deprotection occurred while concentrating the purification fractions containing 0.5% of TFA). 1H NMR (400 MHz, DMSO-d6): 6 ppm 10.18 (s, 1H) 8.93 (s, 1H) 7.81 (dd, J=10.11, 1.77 Hz, 1H) 7.62 (dd, J=7.58, 1.01 Hz, 1H) 7.37 (t, J=8.46 Hz, 1H) 5.56 (s, 1H) 4.39 (dd, J=10.74, 3.16 Hz, 1H) 4.21 (dd, J=10.61, 7.33 Hz, 1H) 3.82-3.88 (m, 1H) 3.50 (s, 3H) 3.42-3.46 (m, 2H). MS (ES) [m+H] calc'd for C17H16FIN4O5, 503; found 503.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([N:9]1[C:21]([CH2:22]O)=[C:20]2[C:11]([C:12](=[O:24])[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=32)=[N:10]1)([CH3:8])([CH3:7])[CH3:6]>ClCCCl>[ClH:3].[C:5]([N:9]1[C:21]([CH2:22][Cl:3])=[C:20]2[C:11]([C:12](=[O:24])[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=32)=[N:10]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)n1nc2c(=O)[nH]c3ccccc3c2c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)n1nc2c(=O)[nH]c3ccccc3c2c1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
Thionyl chloride (6.0 mL, 9.9 g, 82.9 mmol) was added dropwise to a stirring suspension of 2-tert-butyl-1-(hydroxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (4.5 g, 16.6 mmol) in 1,2-dichloroethane (160 mL) and the resulting suspension was stirred at ambient temperature overnight. The volatiles were removed under reduced pressure to yield 5.34 g of 2-tert-butyl-1-(chloromethyl)-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one hydrochloride as a brown solid.
Reaction SMILES: [CH:1](I)=[CH2:2].C([Li])(C)(C)C.[F:9][C:10]([F:20])([F:19])[C:11]([C:13]1[S:17][C:16]([SH:18])=[N:15][CH:14]=1)=[O:12]>CCOCC>[F:20][C:10]([F:9])([F:19])[C:11]([C:13]1[S:17][C:16]([SH:18])=[N:15][CH:14]=1)([OH:12])[CH:1]=[CH2:2]
Reactant: O=C(c1cnc(S)s1)C(F)(F)F
Reactant: C=CI
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: C=CC(O)(c1cnc(S)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of vinyl iodide (1.88 g, 12.2 mmol) in Et2O at −78° C. was added t-butyl lithium (14.3 ml, 1.7 M/pentane, 24.3 mmol). The mixture was stirred at −78° C. for 1 h and warmed up to −30° C. for 5 min. The mixture was cooled back to −78° C. and 2,2,2-trifluoro-1-(2-mercapto-1,3-thiazol-5-yl)ethanone (1.18 g, 5.53 mmol) in Et2O was added. The reaction mixture stirred 30 min at −78° C., brought to 0° C. and partitioned between aqueous NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated and the residue chromatographed on silica gel (toluene/acetone; 90:10) to give the title compound.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].C(N(CC)CC)C.Cl[C:17]([O:19]C)=S.ClCCNCCCl.[CH3:28][O:29][C:30](=[O:41])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[NH2:32]>ClCCl.C(OCC)(=O)C>[CH3:28][O:29][C:30](=[O:41])[CH:31]([NH:32][C:17]([N:5]([CH2:6][CH2:7][Cl:8])[CH2:4][CH2:3][Cl:2])=[O:19])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=1
Reactant: ClCCNCCCl
Reactant: COC(=S)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccc(O)cc1)NC(=O)N(CCCl)CCCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.6 %

Procedure:
bis-(2-Chloroethyl)amine hydrochloride 26 (200 mg, 1.1 mmol) was dissolved in dichloromethane (15 mL) and triethylamine (0.45 mL, 3.3 mmol) was added. The mixture was stirred for 5 minutes at ambient temperature and methyl chlorothioformate (1.32 mmol) was added. The mixture was stirred until no bis-(2-chloroethyl)amine remained by TLC (ethyl acetate). Tyrosine methyl ester (411 mg, 2.1 mmol) was added and the mixture was heated under reflux for 4 hours. The mixture was allowed to cool purified by dry flash column chromatography (silica gel, dichloromethane 200 mL) and concentrated in vacuo to yield prodrug 30 as an orange/brown oil (278 mg, 60%). νmax 3400, 1740, 1660, 1444, 1380, 1145/cm−1; δ 1H (400 MHz, CDCl3) 2.32 (3H, s, CH3) 2.60 (2H, t, J 3.72 Hz, CH2Ar), 2.64 (3H, s, CH3) 3.12–3.25 (9H, m, ArCH2CH, 2×CH2CH2Cl), 6.67 (2H, d, J 5.7 Hz, 2×ArH), 6.9 (2H, d, J 5.7 Hz, 2×ArH), 7.82 (1H, brs, NH);. 13C (100 MHz, CDCl3) 29.8 (CH2), 43.3 (CH2), 44.1 (CH2), 44.2 (CH2), 45.2 (CH2), 46.6 (CH2), 47.1 (CH3) 115.9 (2×CH), 130 (2×CH), 130.1 (C), 155.6 (C), 160.3 (C) 161.5 (C). m/z (Cl) 242 (72%), 227 (45), 183 (75) 152 (100), 121 (45), 108 (35).
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:46]([CH2:56][C:57](O)=[O:58])[C:47]2[C:52]([C:53](=[O:55])[N:54]=1)=[CH:51][CH:50]=[CH:49][CH:48]=2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:46]([CH2:56][C:57]([N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH:14]2[CH2:13][CH2:12][N:11]([C:2]([CH3:1])([CH3:10])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH2:16][CH2:15]2)=[O:58])[C:47]2[C:52]([C:53](=[O:55])[N:54]=1)=[CH:51][CH:50]=[CH:49][CH:48]=2
Reactant: CC(C)(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1,1-dimethylethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B4) (1 equiv), [2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C1) (1.2 equiv), DIPEA (3 equiv) and DMF (1.0 ml) is stirred at room temperature for 5 min. HATU (1.5 equiv) is added in 1 portion and stirred an additional 5 min. The crude reaction mixture is concentrated, filtered through a plug of silica eluted with acetone and evaporated to obtain crude 1,1-dimethylethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl} {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate.
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[H-].[Na+].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[C:21]([F:24])([F:23])[F:22].[CH3:25]N(C)C=O>>[CH3:25][C:5]1([CH2:8][O:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[C:21]([F:24])([F:23])[F:22])[CH2:4][CH2:3][CH2:2][CH2:7][CH2:6]1
Reactant: CN(C)C=O
Reactant: CC1CCC(CO)CC1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CC1(COc2ccc(C=O)cc2C(F)(F)F)CCCCC1
Temperature: 25 °C
Yield: 87 %

Procedure:
30 ml of dried dimethylformamide containing 4-methyl-1-cyclohexanemethanol (1 g, 7.8 mmol) was added to sodium hydride (342.2 mg, 8.58 mmol, 60% dispersed oil) and slowly stirred at room temperature under nitrogen. The mixture was further stirred at room temperature for 30 minutes and added to 5 ml of dried dimethylformamide containing 4-fluoro-3-(trifluoromethyl)benzaldehyde (1.2 g, 7.8 mmol) over 10 minutes. Then, the reaction mixture was stirred at room temperature for 18 hours until the initial product disappeared. 20 ml of ice water was added thereto, and the resulting mixture was extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on the silica gel column (hexane:ethyl acetate=20:1) to afford 4-((methylcyclohexyl)methoxy)-3-(trifluoromethyl)benzaldehyde (1.64 g, yield: 87%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:20])[NH:15]3)[CH:6]=1.[Cl-].[Cl-].[Ca+2]>O.CO.C1COCC1>[OH:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:20])[NH:15]3)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccc(-c2cccc3c2CC(=O)N3)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C1Cc2c(cccc2-c2cccc(CCO)c2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a suspension of NABH4 (600 mg, 16 mmol) in 15% H2O/MeOH (6 mL) under nitrogen at rt was added dropwise a solution of [3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetic acid methyl ester (450 mg, 1.6 mmol) in THF (3 mL). After stirring at rt for overnight, to the reaction was added CaCl2 (300 mg) and stirring was continued for another 5 hours. The reaction was quenched with acetic acid (2 mL), concentrated, diluted with ethyl acetate, washed with 0.5 N HCl (3×15 mL), 10% NaHCO3 (3×15 mL), brine (1×), dried and concentrated. The oily residue was purified to give 384 mg (95%) of 4-[3-(2-hydroxy-ethyl)-phenyl]-1,3-dihydro-indol-2-one.
Reaction SMILES: [ClH:1].CO.[NH2:4][C:5]1[C:14]2[N:15]=[C:16]3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][N:17]3[C:13]=2[C:12]2[C:7](=[CH:8][C:9]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:10][CH:11]=2)[N:6]=1>O1CCOCC1>[ClH:1].[CH2:30]([O:29][C:9]1[CH:8]=[C:7]2[C:12]([C:13]3[N:17]4[CH2:18][CH2:19][NH:20][CH2:21][C:16]4=[N:15][C:14]=3[C:5]([NH2:4])=[N:6]2)=[CH:11][CH:10]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc1n2CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (20 mL of a 4 N solution in 1,4-dioxane) and methanol (20 mL) were added to tert-butyl 6-amino-3-benzyloxy-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate (4.45 g, 9.98 mmol, prepared by the methods described in Example 368 Parts A through I), and the reaction was stirred at ambient temperature overnight. A precipitate was present and was isolated by filtration and washed with cold methanol. The solid was then recrystallized from methanol, isolated by filtration, washed with diethyl ether, and dried overnight under vacuum at 65° C. to provide 3.89 g of 3-benzyloxy-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine hydrochloride as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10](Cl)(=[O:19])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:19])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: Cc1ccc(N)cc1C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)/C=C/c2ccccc2)cc1C
Temperature: 25 °C
Yield: 57.5 %

Procedure:
3,4-Dimethylaniline (5.20 g, 42.9 mmol) was dissolved in 150 mL of THF and treated with trans-cinnamoyl chloride (7.5 g, 45 mmol) with vigorous stirring at room temperature. After 2 hours the mixture was quenched with 10 mL of H2O and extracted with EtOAc (3×100 mL). The combined organics were washed with saturated solution of Na2CO3, brine, dried over MgSO4 and then concentrated in vacuo to yield the title compound as a pure white crystalline solid (6.2 g, 67%). MS (ES) m/e 252 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH:13]1([P:19](=[O:28])([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:20][OH:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N([CH2:34][CH3:35])CC)C>C1C=CC=CC=1>[CH:13]1([P:19]([CH2:20][O:21][C:1](=[O:11])[C:2]2[CH:10]=[CH:9][C:5]([C:6]([O:21][CH2:20][P:19]([CH:35]3[CH2:34][CH2:27][CH2:22][CH2:23][CH2:24]3)([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)=[O:28])=[O:7])=[CH:4][CH:3]=2)([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:28])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCN(CC)CC
Reactant: O=P(CO)(C1CCCCC1)C1CCCCC1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Solvent: c1ccccc1
Product: O=C(OCP(=O)(C1CCCCC1)C1CCCCC1)c1ccc(C(=O)OCP(=O)(C2CCCCC2)C2CCCCC2)cc1

Procedure:
Terephthaloyl chloride (6.1 g, 0.03 mole) in 30 ml benzene was added dropwise to a mixture of dicyclohexyl hydroxymethyl phosphine oxide and triethylamine at 50° C. maximum. The reaction mixture was heated to reflux for 30 minutes and the product was filtered, washed with water and dried; m.p. 226°-228.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.Br[CH2:38][C:39]#[N:40]>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH2:38][C:39]#[N:40])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: N#CCBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Product: N#CCN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
{(3R,4R)-4-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-3-fluoropiperidin-1-yl}acetonitrile was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,4R)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 381) and bromoacetonitrile following General Procedure S.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1(C2C=CC(OC)=C(OC)C=2)[S:10](=[O:12])(=[O:11])[CH2:9][CH2:8][CH2:7][S:6]1(=[O:14])=[O:13].[CH3:25][NH:26]CCC1C=CC(OC)=C(OC)C=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[ClH:1].[CH3:25][NH:26][CH2:2][CH2:3][CH2:4][CH:5]1[S:10](=[O:12])(=[O:11])[CH2:9][CH2:8][CH2:7][S:6]1(=[O:14])=[O:13]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: COc1ccc(C2(CCCCl)S(=O)(=O)CCCS2(=O)=O)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNCCCC1S(=O)(=O)CCCS1(=O)=O
Product: Cl
Temperature: 120 °C

Procedure:
10.4 g of 2-(3-chloropropyl)-2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide are treated with 5.11 g of N-methyl-homoveratrylamine, 30 ml of N-ethyl-N,N-diisopropylamine and 70 ml of dimethylformamide. The solution is heated at 120° C for 6 hours. After evaporation, the residue is worked-up in a manner analogous to that described in Example 5. There is obtained N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl(-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride of melting point 167°-169° C.