Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:42])[NH:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H].C(Cl)(Cl)Cl>CO.C1COCC1.[Pd]>[O:39]1[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][NH:33][C:32]([C:29]2[CH:30]=[CH:31][C:26]([N:23]3[CH2:22][CH2:21][CH:20]([NH:19][C:17]([N:14]4[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]4)=[O:18])[CH2:25][CH2:24]3)=[CH:27][CH:28]=2)=[O:42])[CH2:37][CH2:38]1
Reactant: [H][H]
Reactant: O=C(NCCN1CCOCC1)c1ccc(N2CCC(NC(=O)N3CCN(C(=O)OCc4ccccc4)CC3)CC2)cc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCN1CCOCC1)c1ccc(N2CCC(NC(=O)N3CCNCC3)CC2)cc1

Procedure:
The 4-benzyloxycarbonyl-N-(1-(4-(2-morpholinoethylcarbamoyl)-phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (14.5 g, 25.0 mmol) obtained in Example 15(4) was dissolved in methanol (80 ml) and THF (80 ml), and 10% Pd—C (3.0 g) was added thereto, followed by stirring at room temperature in a hydrogen atmosphere for 17 hours. To the reaction mixture, chloroform was added. After the insoluble material was filtered with Celite, the filtrate was evaporated under reduced pressure, thereby obtaining N-(1-(4-(2-morpholinoethylcarbamoyl)phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (11.2 g, quant.) as a milky-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:6]2.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]c(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
6-Methoxy-3-(1H-pyrazol-3-ylamino)-2H-isoquinolin-1-one (4.7 g, 0.017 mol) and POCl3 (60 ml) were sealed in 3 different bottles (20 ml). The mixture was heated at 150° C. for 15 minutes under microwave irradiation. The mixture was concentrated, the residue was treated with 15 ml MeOH and stirred for 2 hours at room temperature. The solid was collected and dried to give product (3.4 g, 68% yield). LC-MS: 275 (MH+)
Reaction SMILES: C1(S([C:10]2(SC)[CH2:15][C@@H:14]3[C@@:12]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=4)([CH2:13]3)[CH2:11]2)(=O)=O)C=CC=CC=1.C[OH:27].Cl>C(OCC)(=O)C.CCCCCC>[Cl:23][C:18]1[CH:17]=[C:16]([C@@:12]23[CH2:13][C@@H:14]2[CH2:15][C:10](=[O:27])[CH2:11]3)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: CSC1(S(=O)(=O)c2ccccc2)C[C@H]2C[C@@]2(c2ccc(Cl)c(Cl)c2)C1
Reactant: CO
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1C[C@H]2C[C@@]2(c2ccc(Cl)c(Cl)c2)C1
Yield: 99 %

Procedure:
(1R,5R)-3-Benzenesulfonyl-1-(3,4-dichlorophenyl)-3-methylsulfanyl-bicyclo[3.1.0]hexane (1.4 g, 3.3 mmol), methanol (6 mL) and concentrated hydrochloric acid (1.5 mL) were heated to reflux for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (20:80)). The reaction mixture was concentrated under reduced pressure to remove methanol. The pH of the reaction mass was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous layer was extracted with diethyl ether (100 mL). The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 1.1 g of crude oil, which was purified by preparative HPLC to yield 560 mg (70%) of 99% pure product. 1H NMR δ(300 MHz,CDCl3) 0.67-0.70 (1H,t, J=4 Hz), 1.25-1.35 (1H,m), 1.94-2.15 (1H,m), 2.36-2.42 (1H,d ,J=18 Hz), 2.59-2.65 (1H,d,J=18 Hz), 2.83-2.89 (2H,m),6.99-7.03 (1H,dd,J=9.3 Hz), 7.25-7.26 (1H,d,J=3 Hz),7.36-7.39 (1H,d,J=9 Hz). 13CNMR(CDCl3) δ: 215.25, 143.49, 132.55, 130.39, 130.06, 128.07, 125.40, 45.34, 42.08, 27.18, 23.32, 22.24.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:25](=[O:32])[C:26]5[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cccnc4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-nicotinamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (200 mg, 0.64 mmol) and nicotinoyl chloride hydrochloride (282 mg, 1.93 mmol). The title compound was obtained as pink powder (94 mg, 35%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12]O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.C1C=CC(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.[Cl-].[Na+].O>[N:39]([CH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=2)=[N+:40]=[N-:41]
Reactant: Cc1ccc2cc(CO)cnc2c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cc(CN=[N+]=[N-])cnc2c1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
To a solution of (7-methylquinolin-3-yl)methanol 41.5 mg, 0.232 mmol) and DBU (0.063 ml, 0.418 mmol) in DMF (0.8 ml) was added DPPA (0.085 ml, 0.395 mmol). The reaction mixture was stirred for 1.5 h at 23° C. Reaction mixture was poured in brine and extracted twice with ethyl acetate. Organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (Method G) Rt=1.174 min, MS (Method V) [M+H]+=199.2.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:11]#[C:12][CH2:13][CH2:14][CH2:15][CH3:16]>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1C=CC=CC=1>[CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCCC
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCCc1cnnn1Cc1ccccc1

Procedure:
Benzyl azide (0.340 g, 2.55 mmol), 1-hexyne (0.580 ml, 5.05 mmol), Cp*RuCl(PPh3)2 (50 mg, 0.063 mmol). Solvent, benzene; reaction temperature, 80° C.; reaction time, 3 hours; yield, 0.45 g (82%). EI-MS: m/z 216 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:30]=O>C(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]4[O:29][CH2:28][CH2:27][N:26]([CH3:30])[CH2:25]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CNCCO1
Reactant: C=O
Solvent: O
Solvent: O=CO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CN(C)CCO1
Temperature: 95 °C
Yield: 91 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(morpholin-2-ylmethyl)oxy]quinazolin-4-amine (3.32 g, 7.7 mmol) in formic acid (33.2 mL) was added a 37 wt % solution of formaldehyde in water (3.32 mL), and the reaction mixture was heated at 95° C. for 2.5 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was dissolved in methanol and treated with Bio-Rad AG®1-X8 hydroxide form resin until pH 8. Filtration and concentration in vacuo afforded 3.11 g (91%) of the title compound as a yellow-brown solid. 1H NMR (400 MHz, d4-MeOH): 8.46 (s, 1H), 8.14 (d, 1H), 7.73 (dd, 1H), 7.68 (s, 1H), 7.48 (d, 1H), 7.13 (s, 1H), 4.21-4.09 (m, 2H), 4.02 (s, 3H), 4.01-3.91 (m, 3H), 2.96 (m, 1H), 2.75 (m, 1H), 2.35 (s, 3H), 2.22 (m, 1H), 2.11 (t, 1H); MS (EI) for C21H22N4O3Cl2: 449 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:24][CH2:23][C:18]5(OCC[O:19]5)[CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:25])[CH2:3][CH2:2]1.C1COCC1.Cl.C(=O)([O-])O.[Na+]>O.CO>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:24][CH2:23][CH:18]([OH:19])[CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:25])[CH2:2][CH2:3]1
Reactant: Fc1cc(-c2nc3c(o2)CCC2(C3)OCCO2)ccc1OCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OC1CCc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-6,7-dihydro-4H-spiro[1,3-benzoxazole-5,2′-[1,3]dioxolane] (6.00 g) in a mixed solvent of THF (40 mL)-methanol (20 mL)-water (20 mL) was added 6 M hydrochloric acid (17.4 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. To the organic layer was added sodium tetrahydroborate (657 mg), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.93 g).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([CH:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:41])[CH:25]([CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:26][NH:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH2:11]([CH:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:41])[CH:25]([CH2:35][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40]1)[CH2:26][N:27]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH:1]=[O:2])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=CO
Reactant: O=C1OCC(Cc2ccccc2)N1C(=O)C(CNOC1CCCCO1)CC1CCCC1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: O=CN(CC(CC1CCCC1)C(=O)N1C(=O)OCC1Cc1ccccc1)OC1CCCCO1
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of formic acid (45.0 mL, 1193 mmol) and acetic anhydride (90.0 mL, 952 mmol) is stirred at 50° C. for one hour under nitrogen. A second flask is charged with 4-benzyl-3-[2-cyclopentylmethyl-3-(tetrahydro-pyran-2-yloxyamino)-propionyl]-oxazolidin-2-one (21.62 g, 50.2 mmol), Et3N (170.0 mL, 1220 mmol), and anhydrous DCM (450 mL). This second mixture is cooled to 4° C. under nitrogen, and the mixed acid solution is slowly added to the second flask, while maintaining 10° C. The combined mixture is stirred for 30 minutes at 10° C., quenched with saturated, washed with aqueous NaHCO3 solution, and extracted with DCM. The DCM layers are combined, dried over Na2SO4, and concentrated. The crude product is purified by flash chromatography (SiO2, 50% EtOAc in hexane), which gives N-[3-(4-benzyl-2-oxo-oxazolidin-3-yl)-2-cyclopentylmethyl-3-oxo-propyl]-N-(tetrahydro-pyran-2-yloxy)-formamide (20.10 g, 87% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14]=[O:15].[CH3:16][N:17]([CH2:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]2[CH:32]=[C:31]([NH:33][CH3:34])[N:30]=[CH:29][N:28]=2)[CH:23]=[CH:24][CH:25]=1)[CH3:18].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:15])[N:33]([C:31]1[CH:32]=[C:27]([NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][N:17]([CH3:16])[CH3:18])[CH:21]=2)[N:28]=[CH:29][N:30]=1)[CH3:34]
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Reactant: CNc1cc(Nc2cccc(CN(C)C)c2)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3cccc(CN(C)C)c3)ncn2)c1Cl
Temperature: 70 °C
Reaction time: 18 h

Procedure:
2,6-dichloro-3,5-dimethoxyphenylisocyanate (1.25 eq.) is added to a solution of N-(3-dimethylaminomethyl-phenyl)-N′-methyl-pyrimidine-4,6-diamine (93 mg, 0.36 mmol, 1 eq.) in toluene (3 ml), at 70° C. and under an argon atmosphere. The resulting mixture is stirred at 70° C. for 18 h, allowed to cool to RT, and diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 9:1) affords 121 mg of the title compound as a white solid: ESI-MS: 504.9/506.9 [MH]+; tR=3.64 min (purity: 100%, gradient J); TLC: Rf=0.12 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]=1)[CH3:2].CN(C=O)C.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)Cc1c[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cn(Cc2ccccc2)c2ccc(OC)cc12
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
5-Methoxy-1H-indole-3-acetic acid ethyl ester (10.1 g, 41 mmol) was dissolved in 50 mL of THF and 200 mL of DMF and 1.8 g (45 mmol) of 60% NaH/mineral oil were added in portions with cooling. After 0.17 hours, 5 mL (42 mmol) of benzyl bromide was added and stirring maintained for 1.5 hours. The mixture was diluted with water and ethyl acetate, the organic layer separated, washed with water, brine and dried (Na2SO4). The solution was evaporated at reduced pressure and the residue chromatographed on silica gel eluting with a gradient, 25% ethyl acetate/hexane→40% ethyl acetate/hexane, to give 10.8 g (82% yield) of 5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:36]=[CH:37][C:38]3[N:39]([CH:41]=[C:42]([NH:44][C:45]([CH:47]4[CH2:49][CH2:48]4)=[O:46])[N:43]=3)[N:40]=2)=[CH:30][CH:29]=1>CN(C)C(=O)C.O1CCCC1>[CH:47]1([C:45]([NH:44][C:42]2[N:43]=[C:38]3[CH:37]=[CH:36][C:35]([S:34][C:31]4[CH:30]=[CH:29][C:28]([NH:27][C:13]([C:4]5[CH:3]=[C:2]([CH3:1])[N:6]([C:7]6[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=6)[N:5]=5)=[O:15])=[CH:33][CH:32]=4)=[N:40][N:39]3[CH:41]=2)=[O:46])[CH2:48][CH2:49]1
Reactant: Cc1cc(C(=O)O)nn1-c1ccccc1
Reactant: Nc1ccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)cc2)nn1-c1ccccc1
Yield: 63.6 %

Procedure:
Using 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (186 mg, 0.92 mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (80 μL, 0.92 mmol), N-{6-[(4-aminophenyl)thio]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 249, the title compound (201 mg, 64%) was obtained as a white powder.
Reaction SMILES: [O:1]=[C:2]1[CH:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH:3]1C(OC)=O.CS(C)=O.[Na+].[Cl-]>O>[O:1]=[C:2]1[CH:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH2:3]1
Reactant: COC(=O)C1CN2CCN(C(=O)OC(C)(C)C)CC2C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2CCC(=O)C2C1
Temperature: 130 °C

Procedure:
A mixture of 2-tert-butyl 7-methyl 8-oxohexahydropyrrolo[1,2-a]pyrazine-2,7(1H)-dicarboxylate (Example 35B, 131 g, 0.44 mol), dimethyl sulfoxide (530 mL), NaCl (25.6 g, 0.44 mol) and water (32 g, 1.75 mol) was heated to 130° C. and maintained at that temperature for 2 hours. The reaction mixture was cooled, diluted with water (1 L) and extracted with ethyl acetate (1 L×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel eluting with 30-40% ethyl acetate in petroleum ether to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 2.23-2.42 (m, 3H), 2.47-2.60 (m, 1H), 2.60-2.78 (m, 1H), 2.82-2.98 (m, 1H), 3.02-3.10 (m, 1H), 3.32-3.40 (m, 1H), 3.65-3.85 (m, 1H), 3.99-4.20 (bs, 1H), 4.20-4.45 (bs, 1H).
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=3)[NH:18]2)[CH:16]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:17]2[C:26]([CH3:27])([CH3:28])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:7][S:4]([CH:1]4[CH2:3][CH2:2]4)(=[O:6])=[O:5])=[O:30])[CH:23]=3)[NH:18]2)[CH:16]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccc(F)cc1C1Nc2ccc(C(=O)O)cc2CC1(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc2CC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (250 mg, 2.1 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (84 mg, 2.1 mmol). The resulting mixture was stirred at 25° C. for 1 hour. A solution of 2-(5-fluoro-2-methyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (130 mg, 0.42 mmol) and 1,1′-carbonyldiimidazole (130 mg, 0.84 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h. Then the above suspension of cyclopropanesulfonic acid amide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(5-fluoro-2-methyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (40 mg, 23%) as a white solid: LC/MS m/e calcd for C22H25FN2O3S (M+H)+: 417.5, observed: 417.3.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O.O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ICCOc1ccccc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCOc3ccccc3)cc12
Yield: 38.1 %

Procedure:
A mixture of 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) (150 mg, 0.43 mmol), cesium carbonate (280 mg, 0.85 mmol) and (2-Iodo-ethoxy)-benzene (413 mg, 3.87 mmol), in dimethylformamide (6 rill) was stirring at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were washed with a saturated solution of ammonium chloride, water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/ethyl acetate: 0-10%) to yield the title compound (77 mg, 38%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:11]([OH:13])=O)[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C:3]1([CH3:10])[CH3:9].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH3:1][C:2]1([C:11]([Cl:16])=[O:13])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C:3]1([CH3:10])[CH3:9]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(C=C(Cl)Cl)C1(C)C(=O)O
Solvent: c1ccccc1
Product: CC1(C)C(C=C(Cl)Cl)C1(C)C(=O)Cl

Procedure:
0.60 Part of the above carboxylic acid was agitated with 0.38 part of thionyl chloride at 80° C. for 30 minutes in benzene as a solvent to obtain 1,2,2-trimethyl-3-(2',2',-dichlorovinyl)-cyclopropane-carboxylic acid chloride. The acid chloride was agitated with 0.53 part of 3-phenoxybenzyl alcohol in the presence of pyridine at room temperature in benzene as a solvent to obtain 1.02 parts of 3-phenoxybenzyl-1',2',2'-trimethyl-3'-(2",2"-dichlorovinyl)-cyclopropane-carboxylate. The results of the NMR spectrum (60 MHz ) analysis of the so obtained product were as follows:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.C(N(C(C)C)CC)(C)C.[Cl:27][CH:28]([CH3:32])[C:29](Cl)=[O:30]>C1COCC1.C(OCC)(=O)C>[Cl:27][CH:28]([CH3:32])[C:29]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)=[O:30]
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: CC(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cl)C(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.7 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (124 mg, 0.560 mmol) and diisopropylethylamine (DIEA, 111 μL, 0.672 mmol) in THF (5 mL), 2-chloropropionyl chloride (60 μL, 0.620 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 24 hrs and then diluted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL), dried over MgSO4 and the solvent was evaporated in vacuo to afford 2-chloro-N-(3-(quinoxalin-2-yl)phenyl)propanamide (92 mg, 52% yield). LCMS calculated for C17H14ClN3O (M+H): 312.77. found 313. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.52 (1H, br.), 9.53 (1H, s), 8.55 m), 8.12-8.18 (2H, m), 8.05-8.08 (1H, m), 7.82-7.95 (3H, m), 7.55-7.60 (1H, m), 4.75 (1H, q, J=6.8 Hz), 1.68 (3H, d, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10](=[O:18])[CH2:11]C1C=CC=CC=1.[Br:19]Br>C(Cl)Cl>[Br:19][CH2:11][C:10]([C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:18]
Reactant: BrBr
Reactant: O=C(Cc1ccccc1)c1cc(F)c(F)cc1F
Solvent: ClCCl
Product: O=C(CBr)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A 1 L 3-neck round bottom flask was charged with 2′,4′,5′-trifluorophenylacetophenone (49.7 g, 285 mmol) and DCM (350 mL). The flask was equipped with a 250 mL dropping funnel that contained a solution of bromine (14.6 mL, 283 mmol) in DCM (125 mL). This solution was added to the reaction flask over about 1 h at about 23° C. Once addition of the solution was complete, the reaction mixture was stirred for about 1 h at ambient temperature. Ice water was added to the reaction flask and the mixture was stirred for about 15 min. The layers were separated and the organic solution was then washed with water and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a pale yellow solid (70.3 g, 97%): LC/MS (Table 1, Method d) Rt=2.20 min; MS m/z 251.0 (M+H)+.