Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][CH2:20][OH:21].CCN(C(C)C)C(C)C>CN(C=O)C>[N:8]1([C:4]2[N:3]=[C:2]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]3[CH2:19][CH2:20][OH:21])[CH:7]=[CH:6][N:5]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Clc1ccnc(-n2ccnc2)n1
Reactant: OCCC1CCCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OCCC1CCCCN1c1ccnc(-n2ccnc2)n1
Temperature: 80 °C
Yield: 46.1 %

Procedure:
The above synthesis may be carried out as follows: To DMF (100 ml) was added 4-chloro-2-imidazol-1-ylpyrimidine (0.50 g, 2.77 mmol), 2-piperidineethanol (0.359 g, 2.77 mmol), and Hünig's base (0.536 g, 4.15 mmol). After heating at 80° C. for 5 hours, the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH, 19/1) to give 349 mg (46%) of 1-[(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanol (the compound of formula (XVI)), (1H NMR (CDCl3) δ 8.54 (s, 2), 8.11 (d, 1), 7.82 (t, 1), 7.11 (d, 1), 6.44 (d, 1), 3.60 (m, 2), 3.03 (m, 1), 1.77 (m); MS: 274 (M+H)+). To a solution of 1-[(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanol (25 mg, 0.092 mmol) dissolved in DMF (5 ml) was added NaH (60% dispersion in oil, 5.5 mg, 0.14 mmol) followed by piperonyl chloride (17 mg, 0.10 mmol) and t-butyl ammonium chloride. After stirring for 16 hours at 80° C., the solvent was removed in vacuo and the residue was partitioned with saturated NH4C1 and CH2Cl2. The organic layer was separated, dried (MgSO4), the solvent removed in vacuo, and the residue chromatographed (CH2Cl2/MeOH, 19/1) to give 13 mg (35%) of 4-[2-[[(1,3-benzodioxol-5-yl)methoxy]ethyl]piperidin-1-yl]-2-(1H-imidazol-1-yl)pyrimidine (the compound of formula (Icc)); 1H NMR (CDCl3) δ 8.52 (s, 1), 8.05 (d, 1), 7.80 (s, 1), 7.09 (s, 1), 6.73 (m, 3), 6.45 (d, 1), 5.93 (s, 2), 4.30 (s, 2), 3.45 (m, 2), 2.95 (m, 1), 1.55 (m); MS: 408.7 (M+H)+.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:23][C:24]1[CH:25]=[C:26]([N:32]2[CH:40]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[CH:39]3[C:34]([C:35]4[CH:51]=[CH:50][C:49]([C:52]([OH:54])=O)=[CH:48][C:36]=4[CH2:37][CH2:38]3)=[N:33]2)[CH:27]=[CH:28][C:29]=1[C:30]#[N:31].C(O)C.C(N(CC)CC)C.[N:65]1([CH2:70][CH2:71][NH2:72])[CH2:69][CH2:68][CH2:67][CH2:66]1>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26]([N:32]2[CH:40]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[CH:39]3[C:34]([C:35]4[CH:51]=[CH:50][C:49]([C:52]([NH:72][CH2:71][CH2:70][N:65]5[CH2:69][CH2:68][CH2:67][CH2:66]5)=[O:54])=[CH:48][C:36]=4[CH2:37][CH2:38]3)=[N:33]2)[CH:27]=[CH:28][C:29]=1[C:30]#[N:31]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2c2ccc(F)cc2)cc1Cl
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)NCCN5CCCC5)cc4CCC3C2c2ccc(F)cc2)cc1Cl
Reaction time: 0.17 h
Yield: 42 %

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (77 mg, 0.24 mmol) was added to a solution of (±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 2 (89 mg, 0.20 mmol), triethylamine (0.056 mL, 0.40 mmol), and dimethylformamide (2.0 mL) at room temp. After 10 minutes, 2-(pyrrolidin-1-yl)ethanamine (0.051 mL, 0.40 mmol) was added. After 40 minutes, the reaction was quenched with 0.30 mL 3N hydrogen chloride and purified by reverse-phase HPLC (20 to 90% acetonitrile/water/0.05% trifluoroacetic acid). The purified fractions were combined, neutralized with saturated sodium bicarbonate solution, and concentrated until a precipitate formed. The precipitate was filtered, washed with water, and dried to give the title compound (yellow solid, 45.5 mg, 0.084 mmol, 42% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (m, 1H), 1.64 (m, 4H), 1.79 (m, 1H), 2.46 (m, 4H), 2.54 (t, J=7.03 Hz, 2H), 2.91 (m, 2H), 3.35 (q, J=6.64 Hz, 2H), 3.95 (ddd, J=13.57, 11.03, 5.08 Hz, 1H), 5.92 (d, J=11.33 Hz, 1H), 7.15 (m, 6H), 7.65 (d, J=8.59 Hz, 1H), 7.69 (s, 1H), 7.75 (dd, J=8.20, 1.56 Hz, 1H), 8.10 (d, J=8.20 Hz, 1H), 8.47 (t, J=5.86 Hz, 1H). ES-MS m/z 542 (M+H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl.[OH:25][C:26]1[C:35]([N:36]([CH3:38])[CH3:37])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([N:36]([CH3:38])[CH3:37])[C:26]=4[OH:25])[CH2:31]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)nc2ccccc12
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(C(F)(F)F)cc3)nc3ccccc13)C2
Yield: 15 %

Procedure:
Reaction of 2-(4-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 40 (15% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.56 and 2.70 (2s, 6H), 2.85 and 3.10 (2t, 2H), 3.58 and 4.22 (2t, 2H), 4.48 and 5.10 (2s, 2H), 6.33 and 6.83 (2d, 1H), 6.97 and 7.16 (2d, 1H), 7.62-8.55 (m, 7H), 8.74-8.80 (m, 2H); MS (ESI) m/z 493 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28]C)=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@H]2O)=NC=1CC.IC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@H:19]2[O:27][CH3:28])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@H]1O
Solvent: CI
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@H]1OC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1S,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and iodomethane and making non-critical variations provided the title compound as a colorless syrup. IR (liq.) 3447, 2972, 2934, 2907, 2877, 1589, 1565, 1552, 1498, 1471, 1391, 1375, 1196, 1177, 1093 cm−1; OAMS supporting ions at: ESI+ 442.0; MS (EI) m/z 441 (M+); [α]25D=55 (c 0.51, methanol); Anal. Calcd for C24H25Cl2N3O: C, 65.16; H, 5.70; N, 9.50. Found: C, 65.20; H, 5.63; N, 9.43.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.N([O-])=O.[Na+].[ClH:18]>C(O)(=O)C.O>[Cl:18][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOc1ccc2nc(N)sc2c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ccc2nc(Cl)sc2c1
Temperature: 30 °C
Reaction time: 0.33 h
Yield: 61.7 %

Procedure:
20 g (0.103 mol) of 2-amino-6-ethoxy-benzothiazole are dissolved in 100 ml of glacial acetic acid and 52 ml of concentrated hydrochloric acid and whilst cooling with ice the mixture is diazotised with 7.4 g (0.108 mol) of sodium nitrite in 15 ml of water. Then the solution of the diazonium salt is added batchwise to a suspension of 13.6 g (0.137 mol) of copper-I-chloride in 65 ml of concentrated hydrochloric acid and stirred for 20 minutes at 30° C. Then the mixture is diluted with 800 ml of ice water and the crystals formed are suction filtered. To purify them they are chromatographed on silica gel (eluant: petroleum ether/ethyl acetate=6:1). Yield: 61.7% of theory, Melting point: 60-61° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([N:15]1[CH2:47][CH2:46][CH2:45][C@H:16]1[C:17]([NH:19][C@H:20]([C:42]([NH2:44])=[O:43])[CH2:21][S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(O)=O.C(OCC)(=O)C>O>[NH2:1][C@H:2]([C:13]([N:15]1[CH2:47][CH2:46][CH2:45][C@H:16]1[C:17]([NH:19][C@H:20]([C:42]([NH2:44])=[O:43])[CH2:21][S:22][C:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Solvent: O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reaction time: 1 h

Procedure:
To the Boc-Trp-Pro-Cys(Trt)-NH2 (100 gm), added formic acid (800 ml) at temperature of about 20° C. to about 35° C. Stirred for 60 minutes at same temperature and charged ethyl acetate, DM water to the reaction mass and separated the aqueous and organic layers. Washed the organic layer with DM water and separated the layers. Taken organic layer and cooled to about 0° C. to about 10° C. and adjusted pH to 10-12 with 8N aqueous sodium hydroxide solution. Heated the solution to about 25° C. to about 35° C. and separated the organic layer. Concentrated the organic layer under reduced pressure to obtain the residue, which was crystallized from isopropyl ether to obtain H-Trp-Pro-Cys(Trt)-NH2 as white solid material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](N(OC)C)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)Cc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)c1ccccc1
Reaction time: 3 h
Yield: 83.8 %

Procedure:
Under N2, to a mixture of 2-(3,4-dichlorophenyl)-N-methoxy-N-methylacetamide (440 mg, 1.8 mmol) in anhydrous THF was added phenylmagnesium bromide (4.4 mL, 4.4 mmol) at −78° C., and the mixture was stirred for 3 hours. When TLC indicated that the starting material was consumed, the reaction mixture was diluted with EtOAc, washed with water and brine, concentrated, and purified by column chromatography (PE:EtOAc=20:1) to give Intermediate 6 (400 mg, yield 85%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CCN(CC)CC.[CH3:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22].N#N>C1(C)C=CC=CC=1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:19][C:20]([CH3:24])([CH3:23])[C:21]#[C:22][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: C#CC(C)(C)C
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1cc([N+](=O)[O-])cnc1N
Temperature: 70 °C
Yield: 89.2 %

Procedure:
To a solution of 3-bromo-5-nitropyridin-2-amine (1.0 g, 4.6 mmol) in toluene/water (5 mL/2.5 mL), was added Et3N (1.2 mL, 9.2 mmol), Pd(PPh3)2Cl2 (0.3 g, 0.46 mmol), CuI (35 mg, 0.18 mmol) and 3,3-dimethyl-but-1-yne (0.75 g, 9.2 mmol) successively under N2 protection. The mixture was heated at 70° C. for 2.5 h. The solid was filtered and the organic layer was separated. The aqueous layer was exacted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford 3-(3,3-dimethylbut-1-ynyl)-5-nitropyridin-2-amine (0.9 g, 90%). 1H-NMR (CDCl3, 400 MHz) δ 8.87 (d, J=3.2 Hz, 1H), 8.25 (d, J=3.2 Hz, 1H), 5.80 (brs, 2H), 1.36 (s, 9H).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:29][CH2:28][CH2:27]2)=[CH:22][C:21]=1[F:30])=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:29][CH2:28][CH2:27]2)=[CH:22][C:21]=1[F:30])=[O:9]
Reactant: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Agent: Cl
Solvent: CO
Product: O=C(NOCCO)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.6 %

Procedure:
8-(4-Cyclobutyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (2-vinyloxy-ethoxy)-amide (149 mg, 0.36 mmol) was dissolved in methanol (2 mL) and treated with 1M HCl (1.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvents were removed in vacuo and the residue was purified by preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes) to afford the title compound as a yellow solid (16 mg, 11%). LCMS (method A): RT=7.40 min, [M+H]+=385. 1H NMR (DMSO-d6):11.59 (1H, s), 10.60 (1H, s), 8.32 (1H, s), 7.82 (1H, d, J=7.7 Hz), 7.24 (1H, d, J=8.5 Hz), 7.15 (1H, d, J=11.2 Hz), 7.07 (1H, d, J=8.11 Hz), 6.79 (1H, d, J=7.3 Hz), 6.33 (1H, s), 4.73 (1H, s), 3.69 (2H, t, J=4.8 Hz), 3.61 (2H, t, J=5.0 Hz), 3.57 (1H, d, J=8.8 Hz), 2.36 (2H, m), 2.12 (2H, m), 1.96 (1H, m), 1.83 (1H, m).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:19][CH2:18][NH:17][C:11]4([CH2:16]C[CH2:14][O:13][CH2:12]4)[C:9]=3[O:10][C:4]=2[CH:3]=1.I[C:21]1C=CC2C(CCN)=COC=2C=1.CC1C(=O)CCO1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:19][CH2:18][NH:17][C:11]4([CH2:16][CH2:14][O:13][CH:12]4[CH3:21])[C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: Ic1ccc2c3c(oc2c1)C1(CCCOC1)NCC3
Reactant: NCCc1coc2cc(I)ccc12
Agent: CC1OCCC1=O
Product: CC1OCCC12NCCc1c2oc2cc(I)ccc12

Procedure:
Prepared as described for 7-iodo-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran] using 2-(6-iodo-benzofuran-3-yl)-ethylamine and 2-methyldihydrofuran-3(2H)-one. The resulting diasteroisomeric mixture was separated using medium pressure liquid chromatography (140 g amine column) eluting with a gradient of EtOAc in hexanes (from 15% to 70% EtOAc).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][S:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:15]=1[C:16](O)=[O:17]>>[CH3:12][S:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: CSc1cccc(C(F)(F)F)c1C(=O)O
Product: CSc1cccc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=373.1 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methylsulfanyl-6-trifluoromethyl-benzoic acid (intermediate Z).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=c1[nH]cnc2cnc(OCc3ccccc3)cc12
Yield: 84 %

Procedure:
6-Chloro-3H-pyrido[3,4-d]pyrimidine-4-one (9.08 g, 50.0 mmol) was reacted with sodium hydride (60% dispersion on mineral oil, 8.14 g, 203.5 mmol) in benzyl alcohol at 150° C. for 18 hours. The mixture was partitioned between water and ether (water layer at pH14 from the excess sodium hydride) and the layers separated. The aqueous layer was further washed with ether, and then acidified to pH1 with dilute HCl, giving a cream precipitate. This was collected by filtration and dried at 60° C. in vacuo to give 6-benzyloxy-3H-pyrido[3,4-d]pyrimidin-4-one (10.59 g, 84%); δH [2H6]-DMSO 8.71 (1H,s), 7.79 (1H,s), 7.25-7.48 (6H,m), 5.40 (2H,s); m/z (M+1)+254. 6-Benzyloxy-3H-pyrido[3,4-d]pyrimidine-4-one (1.033 g, 4.08 mmol) was reacted with thionyl chloride (10 ml) and dimethyl formamide (2 drops) at reflux under a nitrogen atmosphere for 5 hours, and then left at room temperature overnight. The mixture was concentrated in vacuo, azeotroping twice with toluene to remove the excess thionyl chloride, to give 6-benzyloxy4-chloropyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 8.73 (1H,s), 8.10 (1H,s), 7.25-7.55 (6H,m), 5.41 (2H,s). 6-Benzyloxy-4-chloropyrido[3,4-d]pyrimidine (ca. half the above material, ca. 2 mmol) was reacted with 4-benzyloxyaniline (0.430 g, 2.25 mmol) in acetonitrile (10 ml) according to Procedure A for 5 hours. The resulting brown solid was 6-benzyloxy4-(4-benzyloxyanilino)pyrido[3,4-d]pyrimidine (0.621 g, 71%); δH [2H6]-DMSO 8.99 (1H,s), 8.73 (1H,s), 8.22 (1H,s), 7.71 (2H,d), 7.15-7.55 (10H,m), 7.10 (2H,d), 5.50 (2H,s), 5.13 (2H, s); m/z (M+1)+435.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[C:26]([OH:33])[C:25]=2[CH:34]([CH3:36])[CH3:35])=[O:22])[CH2:16][CH2:15]1.[CH:37](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C.CCCCCC>CO.C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[C:26]([O:33][CH3:37])[C:25]=2[CH:34]([CH3:36])[CH3:35])=[O:22])[CH2:16][CH2:15]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCCSc2nc3ccccc3o2)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc(C(C)C)c(NC(=O)CN2CCN(CCCSc3nc4ccccc4o3)CC2)c1C(C)C
Reaction time: 14 h
Yield: 20.4 %

Procedure:
2-[4-[3-(Benzoxazol-2-ylthio)propyl]piperazin-1-yl]-N-(2,6-diisopropyl-3-hydroxyphenyl)acetamide (150 mg, 0.29 mmol) was dissolved in methanol (2 ml) and acetonitrile (3 ml), then N,N-diisopropylethylamine (227 mg, 1.76 mmol) and a solution of trimethylsilyl diazomethane in hexane (2.0M, 0.88 ml, 1.76 mmol) were added thereto and the mixture was stirred for 14 hours. The reaction solution was concentrated, made alkaline with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (developing solvent, hexane:acetone=7:3) and the resulting crude crystals were recrystallized from ethyl acetate and hexane to provide 31 mg (yield 20%) of the desired compound as colorless powdery crystals.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[CH3:14][N:15]1[C:19]([NH2:20])=[CH:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([NH:20][C:19]1[N:15]([CH3:14])[N:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cn1nccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nccc1NCc1ccccc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
Benzyl bromide (4.97 g) was added dropwise to a dimethylformamide (15 mL) mixture of 1-methyl-1H-pyrazol-5-amine (2.69 g) and potassium carbonate (4.02 g) at a room temperature, and the obtained solution was then stirred at 70° C. for 3 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (Chromatorex NH, hexane:ethyl acetate=2:1), so as to obtain the title compound (1.54 g) in the form of a light yellow oily substance.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.O=[CH:42][CH2:43][NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[C:47]([O:46][C:45]([NH:44][CH2:43][CH2:42][NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1)=[O:51])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCCNC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 1 h

Procedure:
To methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-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)benzoate (1.00 g, 1.84 mmol) in DCE (5 mL) was added tert-butyl 2-oxoethylcarbamate (1.17 g, 7.36 mmol) and tetraisopropoxytitanium (0.700 mL, 2.39 mmol). The reaction mixture was stirred for 1 h, then sodium triacetoxyborohydride (1.17 g, 5.52 mmol) was added. The reaction mixture was stirred for 18 h. The reaction mixture was quenched with sodium bicarbonate and was extracted with DCM (3×40 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate and hexanes (20-100%) as the eluent to provide the title compound as a pale yellow oil. (900 mg, 71%). LCMS: m/e 688.24 (M+H)+, 2.51 min (method 11).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[O:17][C:16](=O)[C:15]2[CH:19]=[C:20]([O:23][CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:22][C:14]=2[N:13]=1.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH2:32]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[N:32]([CH2:31][CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])[C:16](=[O:17])[C:15]2[C:14](=[CH:22][CH:21]=[C:20]([O:23][CH:24]([CH3:26])[CH3:25])[CH:19]=2)[N:13]=1
Reactant: COc1ccc(OC)c(Cc2nc3ccc(OC(C)C)cc3c(=O)o2)c1
Reactant: CN(C)CCCN
Solvent: Cc1ccccc1C
Product: COc1ccc(OC)c(Cc2nc3ccc(OC(C)C)cc3c(=O)n2CCCN(C)C)c1
Yield: 41.5 %

Procedure:
2.84 g (8 mmol) of 2-(2,5-dimethoxyphenylmethyl)-6-isopropoxy-4H-3,1-benzoxazin-4-one and 0.82 g (8 mmol) of 3-dimethylaminopropylamine were heated under reflux for 15 hours in xylene (20 ml). After the xylene was distilled off, the residue obtained was purified by silica gel column chromatography (eluent; 2% ethanol/chloroform) to obtain 1.46 g (42%) of 2-(2,5-dimethoxyphenylmethyl)-3-(3-dimethylaminopropyl)-6-isopropoxy-4(3H)-quinazolinone as an oily substance. Subsequently, 0.22 g of the 2-(2,5-dimethoxyphenylmethyl)-3-(3-dimethylaminopropyl)-6-isopropoxy-4(3H)-quinazolnone was dissolved in ether (15 ml) and to the resulting soluion, there was added an ethanolic solution containing 0.07 g (0.6 mmol) of maleic acid. The thus obtained solution was allowed to stand for one day. The precipitated colorless crystals were collected by filtration to obtain 0.25 g of the maleate which is the desired compound.