Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:8]=2)[N:3]=1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: COc1ccccc1CN
Reactant: NCCN1CCOCC1
Product: COc1ccccc1CNc1ccc2cc(NCCN3CCOCC3)ccc2n1

Procedure:
The title compound, MS: m/e=393.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and N-(2-aminoethyl)morpholine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:24][C:25]([OH:27])=[O:26])[CH:21]=3)[CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:24][C:25]([OH:27])=[O:26])[CH:21]=3)[CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(O)Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(S(=O)(=O)NCC2Cc3ccc(CC(=O)O)cc3C2)cc1
Yield: 79.4 %

Procedure:
1.95 g of [2-[(4-nitrophenyl)sulfonylaminomethyl)indan-5-yl]acetic acid obtained in Example 22 was dissolved in 50 ml of methanol and added with 200 mg of 10% palladium on carbon, followed by stirring for 2 hours in the stream of hydrogen gas. The catalyst was removed by filtration, the filtrate was condensed and the residue was recrystallized from ethanol to obtain 1.43 g of crystals. Yield: 79%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8](C3CCCCO3)[C:5]2=[CH:6][N:7]=1.[C:18]([C:20]1[CH:21]=[C:22]([N:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=1)#[N:19].[N:48]1[CH:53]=[CH:52][CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=1>>[N:35]1([C:22]2[CH:21]=[C:20]([CH:25]=[C:24]([C:10]3[C:4]4[C:5](=[CH:6][N:7]=[C:2]([C:50]5[CH:49]=[N:48][CH:53]=[CH:52][CH:51]=5)[CH:3]=4)[NH:8][N:9]=3)[CH:23]=2)[C:18]#[N:19])[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C#N)cc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: Brc1cc2c(I)nn(C3CCCCO3)c2cn1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Product: N#Cc1cc(-c2n[nH]c3cnc(-c4cccnc4)cc23)cc(N2CCNCC2)c1
Yield: 19 %

Procedure:
Following the Suzuki coupling procedure of Example 159, 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl 4-(3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate were reacted. The product was coupled with 3-pyridineboronic acid pinacol ester by the Suzuki coupling procedure of Example 10 and deprotected by the procedure of Example 225. The mixture was purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 37 mg (19%) of 240 over three steps. ESI MS m/z 382.2 (M+1). 1H NMR (400 MHz, DMSO): 9.41 (s, 1H), 9.23 (s, 1H), 8.68-8.59 (m, 2H), 8.55 (d, J=7.8 Hz, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.56-7.50 (m, 1H), 7.43 (s, 1H), 3.26-3.23 (m, 4H), 2.87-2.81 (m, 4H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:8][C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[O:18])[N:4]=1
Reactant: Cc1[nH]nc(N)c1Cl
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(N)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as colorless oil. 1H NMR (400 MHz, CDCl3): 7.02-7.08 (m, 2H), 6.94-7.0 (t, 2H), 4.85 (s, 2H), 4.2 (s, 2H), 3.80-3.88 (m, 4H), 3.14-3.34 (m, 4H), 2.34 (s, 3H). MS (ES) M+H expected 317.37, found 318.1. MS (ES) M+H expected 351.81, found 352.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:7][CH:6]=1)=[O:4].Cl.[C:15](=N)(OCC)[CH3:16]>N1C=CC=CC=1>[CH3:15][C:16]1[O:11][C:10]([C:8]2[S:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[N:12][N:13]=1
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2nnc(C)o2)s1
Temperature: 25 °C

Procedure:
A stirred suspension of 5-methoxycarbonyl-2-thiophenecarboxylic acid hydrazide (548 mg, 2.74 mmoles) and ethyl acetimidate hydrochloride (372 mg, 3.01 mmoles) in 10 ml of pyridine was refluxed for four hours, cooled to room temperature and evaporated in vacuo. The residual oily solid was dissolved in ethyl acetate and washed with water, 1N hydrochloric acid and 5% sodium bicarbonate. The ethyl acetate was dried magnesium sulfate) and evaporated in vacuo to a pale tan solid (242 mg, 39%), m.p. 142-5° C. This material was used directly without further purification. Exact Mass: 224.0253, Calculated: 224.0256; EIMS (m/z): 224 (M+, base), 193 (M+ --CH3O, 33%), 169 (C7H5O3S, 83%); 1HNMR (DMSO-d6) delta, 7.88 (1H, d, J=3.9 Hz), 7.80 (1H, d, J=3.9 Hz), 3.87 (3H, s), 2.58 (3H, s); ir (potassium bromide): 1705, 1571, 1291, 1101, 751 cm-1.
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5]2([CH:11]3[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]3)[CH2:7]2)[CH2:4][C:3]1=O.Cl.[CH2:16](O)C>>[CH3:1][CH:2]1[S:6][C:5]2([CH:11]3[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]3)[CH2:7]2)[CH2:4][C:3]1=[CH2:16]
Reactant: CC1SC2(CC1=O)CN1CCC2CC1
Reactant: CCO
Agent: Cl
Product: C=C1CC2(CN3CCC2CC3)SC1C

Procedure:
5'-Methyl-4'-methylenespiro[1-azabicyclo[2.2.2]-octane-3,2'-thiolane] was prepared in much the same manner as in Example 5 by using 5'-methylspiro[1-azabicyclo[2.2.2]-octane-3,2'-thiolan]-4'-one. It was dissolved in ethanol, and then convereted to hydrochloride by addition of ethanolic hydrogen chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:21].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[NH:54][C:55](=[O:63])[C:56]2[CH2:62][O:61][CH2:60][CH2:59][C:57]=2[N:58]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:51][CH2:52][C:53]3[NH:54][C:55](=[O:63])[C:56]4[CH2:62][O:61][CH2:60][CH2:59][C:57]=4[N:58]=3)=[O:18])[CH2:13][CH2:14]2)=[O:8])=[CH:5][C:4]=1[CH3:21]
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)COCC4)CC2)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.5 %

Procedure:
A solution of [4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-acetic acid (0.10 g, 0.34 mmol), EDCl (0.08 g, 0.41 mmol), HOBT (0.06 g, 0.41 mmol) and triethylamine (0.17 g, 1.7 mmol) in 10 mL of DMF was stirred at ambient temperature for 20 min., then 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.06 g, 0.34 mmol) was added. The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was diluted with 50 mL of water, extracted with DCM (100 mL) and the combined organic layers were washed with saturated aqueous NaHCO3 solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide crude product. Purification by flash chromatography gave the title compound (42.8 mg, 0.09 mmol) as a yellow solid. MS (ESI) m/z 454.8 (M+H+); HPLC (Insertsil ODS3 100×3 mm C-18 column: mobile phase: 5-95% acetonitrile/water with 0.1% TFA, at 1 mL/min over 7.75 min.), t=1.21 min. 1H NMR (400 MHz, dichloromethane-d2) δ ppm 1.77-1.97 (m, 4H), 2.28 (br. s., 3H), 2.42-2.55 (m, 2H), 2.64-2.77 (m, 2H), 2.90-3.11 (m, 3H), 3.17-3.24 (m, 2H), 3.25-3.36 (m, 1H), 3.93 (br. s., 3H), 4.31-4.41 (m, 2H), 4.48-4.65 (m, 3H), 6.89-7.02 (m, 1H), 7.78 (br. s., 1H), 7.84 (d, J=8.59 Hz, 1H), 8.20 (br. s., 1H), 10.84 (s, 1H). HRMS calculated for C24H31N4O5: 455.2294 (M+H). found (ESI, [M+H]+): 455.2311.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][C:11](O)=[O:12])=[CH:5][CH:4]=1.CN(C)C=O.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][C:11]([Cl:35])=[O:12])=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OCc1ccc(OC)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCC[C@H](CC(=O)Cl)OCc1ccc(OC)cc1
Temperature: -10 °C

Procedure:
To a solution of acid 34 (500 mg, 1.37 mmol) in DCM (5 mL) was added dimethylformamide (DMF) (100 mg, 1.37 mmol), and the resulting mixture was cooled to −10° C. Oxalyl chloride (174 mg, 1.37 mmol) in DCM (5 mL) was added dropwise. The solution was allowed to warm to room temperature over 1 h. After TLC analysis showed no acid present, the mixture was concentrated in vacuo and used without further purification.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:11][C:12]1[S:13][C:14]([S:18](Cl)(=[O:20])=[O:19])=[C:15]([CH3:17])[N:16]=1)(=[O:10])[CH3:9].[CH:22]([O:35][C:36]1[C:37]2[C:49](=[O:50])[N:48]([CH2:51][C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[CH2:47][C:38]=2[C:39]([OH:46])=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCOC(C)=O.CCCCCC>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:22]([O:35][C:36]1[C:37]2[C:49](=[O:50])[N:48]([CH2:51][C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[CH2:47][C:38]=2[C:39]([O:46][S:18]([C:14]2[S:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[N:16][C:15]=2[CH3:17])(=[O:19])=[O:20])=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1c2c(c(O)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)Oc2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.4 %

Procedure:
Triethylamine (50 g), DMAP (catalytic amount) and 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride (25.5 mg, 0.10 mmol) were added to 0.034 mmol 45. The reaction mixture was stirred at room temperature for 18 hours under an inert atmosphere. The reaction was monitored by TLC (EtOAc/hexane 3/7) (Rf 44=0.5, Rf 45=0, Rf 272=0.2) and LC/MS. After completion of the reaction, the mixture was diluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethylacetate/hexane—3/7) to afford 2-acetylamino-4-methyl-thiazole-5-sulfonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 272 (18.9 mg, 79%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CCCC(OC)=O)N=2)CC1)=O)(C)(C)C>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: COC(=O)CCCCl
Agent: COC(=O)CCCn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: COC(=O)CCCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound (0.003 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using methyl 4-chlorobutyrate (0.8 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(3-methoxycarbonyl-propyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C18H22ClN3O2, 347.14; found, m/z 348.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.31 (m, 4H), 4.07 (t, J=6.6 Hz, 2H), 3.52 (s, 3H), 2.97-2.94 (m, 2H), 2.88-2.84 (m, 4H), 2.70-2.66 (m, 2H), 2.25 (t, J=6.6 Hz, 2H), 1.98-1.95 (m, 2H).
Reaction SMILES: [NH:1]1[C:11]2[C:12]3[C:3]([CH2:4][NH:5][CH2:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)=[CH:2]1.C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][C:23](Cl)=[O:24].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:20][CH2:21][CH2:22][C:23]([N:5]1[CH2:4][C:3]2=[CH:2][NH:1][C:11]3[C:12]2=[C:7]([CH:8]=[CH:9][CH:10]=3)[CH2:6]1)=[O:24]
Reactant: c1cc2c3c(c[nH]c3c1)CNC2
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCCl)N1Cc2cccc3[nH]cc(c23)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline (3.24 g), described in Example 5, in chloroform (350 ml), triethylamine (6.0 ml) is added, followed by dropwise addition of 3-chloropropionyl chloride (4.2 ml). The mixture is stirred at room temperature for 2.5 hr. Aqueous sodium bicarbonate is added and the stirring is continued for 15 minutes. The layers are separated and the organic phase washed with water, dried and concentrated to give 4-(3-chloropropionyl)-1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline, mp 158°-161°C after recrystallizaton from chloroform.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([CH3:13])[NH:8]2.Cl.CN(C)CCCN=C=NCC.[CH3:27][N:28]1[C:33](=[O:34])[CH:32]=[C:31]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:30]=[C:29]1[CH2:41][C:42]([O-])=[O:43].[Na+].O>CN(C)C=O.N1C=CC=CC=1>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([CH3:13])[N:8]2[C:42](=[O:43])[CH2:41][C:29]1[N:28]([CH3:27])[C:33](=[O:34])[CH:32]=[C:31]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:30]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: CC1Cc2c(cccc2OC(F)F)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2c(OC(F)F)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.4 %

Procedure:
125 mg of 4-difluoromethoxy-2-methyl-2,3-dihydro-1H-indole [reference example 11d] and 193 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 242 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2d of example 4d) in 6 ml of N,N-dimethylformamide and 6 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours, and then 25 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with a 0.1N hydrochloric acid solution, water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (90/10: v/v), so as to give 170 mg of 2-{2-[4-(difluoromethoxy)-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].OC[CH:11]1[CH2:16][NH:15][C:14](=[O:17])[CH2:13][CH2:12]1.N1C=CN=C1.CN([CH:26]=[O:27])C>>[Si:1]([O:27][CH2:26][N:15]1[CH2:16][CH2:11][CH2:12][CH2:13][C:14]1=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: O=C1CCC(CO)CN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OCN1CCCCC1=O
Temperature: 22 °C
Reaction time: 36 h

Procedure:
To a solution of 5.8 g tert-butyl(dimethyl)silyl chloride and 5.0 g of 5-hydroxymethyl-2-piperidone in 150 ml of anhydrous DMF was added 5.3 g of imidazole. After stirring for 36 hours at 22° C., the mixture was evaporated under vacuum to remove most of the DMF. Following the addition of water, the residue was extracted with three portions of ethyl acetate. The combined organic extracts were washed with water, 0.5N HCl, water and brine, dried over magnesium sulfate and evaporated. The resulting oil was chromatographed over silica gel eluting with 5% methanol in chloroform to give 4.7 g of the title compound as an oil: MS m/z 244 (M+), 186 [M+ -58(t-butyl)]; 300-MHz 1H NMR (CDCl3) δ0.05 (s, 6 H), 0.85 (s, 9 H), 1.42-1.57 (m, 1 H), 1.77-1.88 (m, 1 H), 1.89-2.03 (m, 1 H), 2.25- 2.45 (m, 2 H), 3.03 (t, J=9 Hz, 1 H), 3.30-3.41 (m, 1 H), 3.45-3.59 (m, 2 H), 5.95 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.ClC1N=CC(N2C3N=C(N4CCOCC4)N=C(C4C=NC(N(CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=NC=4)C=3CC2)=CC=1.[C:95]([N:98]1[CH2:103][CH2:102][NH:101][CH2:100][CH2:99]1)(=[O:97])[CH3:96]>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([N:101]6[CH2:102][CH2:103][N:98]([C:95](=[O:97])[CH3:96])[CH2:99][CH2:100]6)[CH:7]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(Cl)c3)cn2)cc1
Reactant: CC(=O)N1CCNCC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(N4CCN(C(C)=O)CC4)c3)cn2)cc1
Yield: 84.2 %

Procedure:
Using {5-[7-(2-chloro-pyridin-4-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.31 mmol) obtained in Step A in Example 1-D-69 instead of {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine, and N-acetylpiperazine (59 mg, 0.46 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Example 1-D-48, amination was carried out, to obtain a crude product of 1-{4-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-piperazin-1-yl}-ethanone as a yellow solid (194 mg, 85%), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-70) as a yellow powder (71 mg, 46%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=[CH:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C:8](=[O:10])[CH3:9])[CH2:6][CH2:5]1.[CH2:25]([Mg]Br)[CH3:26].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=[CH:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C@:8]([CH2:25][CH3:26])([OH:10])[CH3:9])[CH2:6][CH2:5]1
Reactant: CC[Mg]Br
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@](C)(O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Yield: 48.5 %

Procedure:
To a solution of 100 mg (0.303 mmol) 7β-methyl-5α-4-azapregn-1-ene-3,20-dione in 10 ml dry tetrahydrofuran at -40° C. under N2 was added 15 eq ethylmagnesium bromide (4.5 mmol) in ether. The reaction was stirred and allowed to warm to RT over 18 hours. Aqueous ammonium chloride (5 ml) was added and the solvents were evaporated. The residue was partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The product was purified via HPLC on a 19×300 mm 8 micron silica column using 5% isopropanol/hexane at 20 ml/min to yield 53 mg (0.147 mmol, 49% yield) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1.N1C=CC=CC=1.[S:21](Cl)(Cl)=[O:22].[CH2:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH3:26]>O1CCCC1>[CH3:31][S:28]([N:27]([CH2:25][CH3:26])[S:21]([N:2]([CH3:1])[C:3](=[O:14])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:12])[CH3:13])[CH:6]=1)=[O:22])(=[O:30])=[O:29]
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)Oc1cccc(C(C)C)c1
Reactant: CCNS(C)(=O)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCN(S(=O)N(C)C(=O)Oc1cccc(C(C)C)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-isopropylphenyl methylcarbamate (3.9 g, 0.02 mol) in 20 ml dry tetrahydrofuran, was added pyridine (1.9 g, 0.024 mol) followed by thionyl chloride (2.5 g, 0.021 mol). The mixture was stirred at room temperature for 5 hours. Pyridine (1.9 g, 0.024 mol) was added and followed by N-ethylmethanesulfonamide (2.7 g, 0.022 mol) and stirring of the reaction mixture was continued for an additional 10 hours.
Reaction SMILES: C([NH:8][C:9]1[C:29]2[CH2:28][CH2:27][CH2:26][C:25]=2[C:12]2[O:13][CH2:14][CH:15]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:11]=2[C:10]=1[CH3:30])C1C=CC=CC=1>CCCCCC.C(OCC)(=O)C>[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([CH:15]2[CH2:14][O:13][C:12]3[C:25]4[CH2:26][CH2:27][CH2:28][C:29]=4[C:9]([NH2:8])=[C:10]([CH3:30])[C:11]2=3)=[CH:21][CH:20]=1)([CH3:24])[CH3:23]
Reactant: Cc1c(NCc2ccccc2)c2c(c3c1C(c1ccc(C(C)C)cc1)CO3)CCC2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(N)c2c(c3c1C(c1ccc(C(C)C)cc1)CO3)CCC2
Yield: 91 %

Procedure:
Using N-benzyl-3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-5-amine synthesized in Reference Example 290, the title compound was synthesized in the same manner as in Reference Example 30. Yield 91%. Melting point: 112-113° C. (hexane-ethyl acetate).
Reaction SMILES: [CH:1]([Mg]Cl)([CH2:3][CH3:4])[CH3:2].[CH3:7][C:8]1[N:9]=[C:10]([C:28]#N)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:12]=2[N:13]=1.[O:30]1CCCC1>>[CH3:2][CH:1]([CH2:3][CH3:4])[C:28]([C:10]1[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:12]=2[N:13]=[C:8]([CH3:7])[N:9]=1)=[O:30]
Reactant: Cc1cc(C)c(-n2c(C)c(C)c3c(C#N)nc(C)nc32)c(C)c1
Reactant: CCC(C)[Mg]Cl
Reactant: C1CCOC1
Product: CCC(C)C(=O)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of sec-butyl magnesium chloride (1.5 ml, 3.0 mmol, 2 M in diethyl ether) in 24 ml of dry tetrahydrofuran was added 2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile (0.814 g, 2.67 mmol) at room temperature and stirred for 5 hours. The mixture was quenched with 5 ml of 2N HCl, neutralized with saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow solid. The solid was purified through silica gel column chromatography using chloroform as eluent to give 0.884 g (90%) of the title compound as yellow crystals, mp 133-135° C.