Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][CH:36]1[CH2:38][CH2:37]1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:35][CH:36]2[CH2:38][CH2:37]2)[C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=2)=[O:7])=[CH:26][CH:27]=1
Reactant: BrCC1CC1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(I)c3)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(I)c1)cc(=O)n2CC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.2 %

Procedure:
A solution of 6-(4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1H-quinolin-2-one (9.68 g, 19.9 mmol), prepared as described in PCT international patent application publication number WO 97/21701 (published Jun. 19, 1997) (3.10 g, 7.87 mmol) in DMF (70 mL) was treated with cesium carbonate (23.1 g, 19.9 mmol) and (bromomethyl)cyclopropane (5.37 g, 39.8 mmol). The reaction mixture was stirred at room temperature for 12 hours, diluted with dichloromethane (75 mL), and washed with 1N HCl (2×50 mL) and brine (100 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to give a black residue. Purification by flash column chromatography (silica, ethyl acetate:petroleum ether 1:9-3:7) gave 6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-iodo-phenyl)-1H-quinolin-2-one (6.79 g, 63%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:16])=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F-].[K+].[SH:19][C:20]1[S:21][C:22]([S:25][CH3:26])=[N:23][N:24]=1>CN(C=O)C>[Cl:16][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[Cl:15])[N:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:2]([S:19][C:20]1[S:21][C:22]([S:25][CH3:26])=[N:23][N:24]=1)=[N:3]2
Reactant: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: CSc1nnc(S)s1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nnc(Sc2nc3cc(Cl)c(Cl)cc3nc2C(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6,7-trichloro-3-isopropylquinoxaline (69 mg, 0.25 mmol) in DMF (4 ml) was added potassium fluoride 40% wt on alumina (109 mg, 0.75 mmol) followed by addition of 2-mercapto-5-methylsulfanyl-1,3,4-thiadiazole (44 mg, 0.26 mmol). The reaction was stirred overnight at room temperature. The product was purified by flash column chromatography using ethyl acetate:hexanes 1:20 to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.O[CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:30]4[CH2:31][CH2:32][N:33]([CH2:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[CH2:34][CH2:35]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCN(Cc4ccccc4)CC3)cc2)cc1
Yield: 78.6 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), 4-hydroxy-1-benzylpiperidine (1.15 g, 6.00 mmol), triphenylphosphine (1.57 g, 6.00 mmol), and DEAD (6.00 mmol) were converted to product by the procedure of Example 1 to give 1.33 g of the title compound. Yield: 79%. MS(FD) 563(M+). IR (CHCl3) ν max 3030, 3011, 2955, 2846, 1645, 1597, 1476, 1254, 1166.
Reaction SMILES: [CH2:1]([N:8]([CH3:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.Cl>[CH2:1]([N:8]([CH3:19])[C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N(C)Cc1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(N)cc1N(C)Cc1ccccc1

Procedure:
SnCl2-dihydrate (1117 mg, 4.95 mmol) is added to a solution of N-Benzyl-N,2-dimethyl-5-nitro-aniline (247 mg, 0.96 mmol) in methanol (10 mL) and conc. HCl (1 mL). After boiling under reflux for 2.5 h, volatiles are evaporated under reduced pressure and the residue is partitioned between EtOAc and water, the pH being adjusted to approx. 10 by the addition of 2N NaOH. The organic layer is washed with sat. brine, dried (Na2SO4), and evaporated. Chromatography of the residue (silica gel, hexanes/EtOAc 3:2) yields N3-benzyl-N3,4-dimethyl-benzene-1,3-diamine.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.[N:15]1([CH2:21][CH2:22][N:23]([CH2:35][CH2:36][CH3:37])[CH:24]2[CH2:33][CH2:32][C:31]3[C:30]([OH:34])=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:25]2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[OH:34][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[CH2:32][CH2:33][CH:24]([N:23]([CH2:35][CH2:36][CH3:37])[CH2:22][CH2:21][N:15]1[CH2:20][CH2:19][N:18]([CH2:3][C:4]3[CH:13]=[CH:12][C:11]([OH:14])=[C:10]4[C:5]=3[CH:6]=[CH:7][CH:8]=[N:9]4)[CH2:17][CH2:16]1)[CH2:25]2
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: Cl
Product: CCCN(CCN1CCN(Cc2ccc(O)c3ncccc23)CC1)C1CCc2c(O)cccc2C1
Yield: 77.5 %

Procedure:
This compound was prepared following the procedure H in which compound 11 (0.18 g, 0.8 mmol) and 9b (0.23 g, 0.72 mmol) were used to afford 12b as yellow solid (0.265 g, 59%). 1H NMR of salt (400 MHz, DMSO-d6) δ ppm 0.84-0.87 (t, 3H, J=6 Hz), 1.79-1.81 (bs, 4H), 2.298 (bs, 1H), 2.476-2.48 (m, 2H), 2.74 (s, 2H), 2.96-3.02 (t, 1H, J=12 Hz), 3.122 (bs, 3H), 3.34-3.65 (m, 12H), 6.50-6.52 (d, 1H, J=8 Hz), 6.55-6.57 (d, 1H, J=8 Hz), 6.93-6.96 (t, 1H, J=6 Hz), 7.06-7.08 (d, 1H, J=8 Hz), 7.32-7.34 (d, 1H, J=8 Hz), 7.44-7.46 (m, 1H), 8.66-8.68 (d, 1H, J=8 Hz), 8.77-8.78 (d, 1H, J=4 Hz). The hydrochloride salt mp 252-255° C. Analysis calculated for (C29H43N4O4.5, 4HCl) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[N:8][C@H:9]([C:14]([O-:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>>[CH2:24]([O:23][C:21]([N:8]1[C@@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:14](=[O:16])[O:15][C@H:7]1[C:6]1[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(C=N[C@@H](CC(C)C)C(=O)[O-])cc1
Agent: [Na+]
Product: COc1ccc([C@@H]2OC(=O)[C@H](CC(C)C)N2C(=O)OCc2ccccc2)cc1

Procedure:
(2S,4S)-N-Benzyloxycarbonyl-4-isobutyl-2-(4'-methoxyphenyl)-1,3-oxazolidin-5-one (15) was prepared from sodium N-(para-methoxybenzylidene)-(L)-leucinate (2.71 g, 10.0 mM) and benzyl chloroformate (1.43 mL, 10.0 mM) following general procedure C and obtained as a colourless oil after purification by flash column chromatography, using 25% ethyl acetate/petrol as eluant (3.21 g, 84%, single diastereomer): [α]D20 -30.0 (c 1.0, CHCl3); IR (CHCl3): 1795, 1715 cm-1 ; 1H NMR (200 MHz, CDCl3): δ 6.89-7.38 (m, 9H), 6.71 (s, 1H), 5.20 (s, 2H), 4.47 (t, J=7 Hz, 1H), 3.82 (s, 3H), 1.57-1.98 (m, 3H), 0.88-0.92 (m, 6H); 13C NMR (50.3 MHz, CDCl3): δ 172.5, 160.4, 154.0, 135.3, 129.2, 128.6, 128.3, 127.4, 113.9, 88.8, 68.1, 55.3, 54.4, 42.1, 24.5, 22.3, 22.2; LRMS (NH3): 384 (MH+); HRMS: calcd for C22H26NO5 (MH+): 384.1811; found: 384.1811.
Reaction SMILES: [C:1](C1C=CC(C(C2C(=O)CCCC=2OC)NC(NC2C=C(C(F)(F)F)C=CN=2)=O)=CC=1)#N.[C:33]([C:35]1[CH:36]=[CH:37][C:38]([CH:41]([C:56]2[C:61](=[O:62])[CH2:60][CH2:59][CH2:58][C:57]=2[OH:63])[NH:42][C:43]([NH:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=2)=[O:44])=[N:39][CH:40]=1)#[N:34]>>[C:33]([C:35]1[CH:36]=[CH:37][C:38]([CH:41]([C:56]2[C:57](=[O:63])[CH2:58][CH2:59][CH2:60][C:61]=2[O:62][CH3:1])[NH:42][C:43]([NH:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:54])([F:55])[F:53])[CH:47]=2)=[O:44])=[N:39][CH:40]=1)#[N:34]
Reactant: COC1=C(C(NC(=O)Nc2cc(C(F)(F)F)ccn2)c2ccc(C#N)cc2)C(=O)CCC1
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CCCC2=O)nc1
Product: COC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cn2)C(=O)CCC1

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-methoxy-6-oxocyclohex-1-enyl)methyl)-3-(4-(trifluoromethyl)pyridin-2-yl)urea (intermediate 25) using 1-((5-cyanopyridin-2-yl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl) urea (intermediate 28, 330 mg, 0.767 mmol) as starting material. Yield: 203 mg; ESI mass spectrum [M+H]+=445, Retention time HPLC: 1.05 min (V011_S01).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[C:8]([C:7]1[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)[CH:6]=1)#[N:9]
Reactant: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1Cl
Reactant: C1COCCN1
Product: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1N1CCOCC1

Procedure:
A mixture of 10 g 2-chloro-3-cyano-5,4'-bipyridine-1'-oxide and 40 ml morpholine is heated for 10 minutes at 70° C.-80° C. Subsequently, the mixture is evaporated to dryness under vacuum at an 80° C. bath temperature and the residue is collected, washed carefully with water and dried at 110° C. The product is refluxed for 1 hour with 150 ml dichloromethane, filtered off with suction, dried once again at 110° C. and crystallized from n-butyl acetate. Yield: 9.27 g (75% of the theoretical yield), with a melting point of 234° C.-236° C.
Reaction SMILES: C(OC(=O)[N:7]([CH:15]1[CH2:17][CH2:16]1)[C@@H:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[F:14])(C)(C)C.Cl[C:20]1[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1>>[CH:15]1([NH:7][C@@H:8]2[CH2:13][CH2:12][N:11]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=3)[CH2:10][C@@H:9]2[F:14])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N(C1CC1)[C@@H]1CCNC[C@@H]1F
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CC[C@@H](NC3CC3)[C@@H](F)C2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[(3S,4R)-3-fluoro-piperidin-4-yl]-carbamic acid tert-butyl ester and 2-chloro-5-ethyl-pyrimidine following a procedure analogous to that described for Intermediate 73.
Reaction SMILES: Cl[S:2]([NH:5][C:6](=[O:11])[O:7][CH2:8][CH2:9]Cl)(=[O:4])=[O:3].[CH2:12]([C@H:14]1[C@@H:18]([C:19]2[N:23]3[C:24]4[CH:30]=[CH:29][N:28]([S:31]([C:34]5[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=5)(=[O:33])=[O:32])[C:25]=4[N:26]=[CH:27][C:22]3=[N:21][N:20]=2)[CH2:17][C@@H:16]([NH2:41])[CH2:15]1)[CH3:13]>C(Cl)Cl>[CH2:12]([C@H:14]1[C@@H:18]([C:19]2[N:23]3[C:24]4[CH:30]=[CH:29][N:28]([S:31]([C:34]5[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=5)(=[O:33])=[O:32])[C:25]=4[N:26]=[CH:27][C:22]3=[N:21][N:20]=2)[CH2:17][C@@H:16]([NH:41][S:2]([N:5]2[CH2:9][CH2:8][O:7][C:6]2=[O:11])(=[O:4])=[O:3])[CH2:15]1)[CH3:13]
Reactant: O=C(NS(=O)(=O)Cl)OCCCl
Reactant: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Solvent: ClCCl
Product: CC[C@@H]1C[C@H](NS(=O)(=O)N2CCOC2=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a mixture of 2-chloroethyl chlorosulfonylcarbamate (prepared as detailed in Bioorg. Med. Chem. Lett., 2006 16, 3367-3370; 0.052 g, 0.236 mmol) and (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.100 g, 0.236 mmol, Example #8 Step M) in DCM (2.4 mL) was added TEA (0.098 mL, 0.71 mmol) and the reaction mixture was stirred at ambient temperature for about 1 h. The reaction mixture was concd under reduced pressure to give N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide (0.098 g, 65%) as a light brown solid: LC/MS (Table 1, Method a) Rt=2.18 min; MS m/z 574 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[OH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1
Reactant: COC(=O)c1ccc(COC(C)=O)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CO)cc1OC
Reaction time: 1 h
Yield: 53 %

Procedure:
The whole of the crude methyl 4-acetoxymethyl-2-methoxybenzoate thus obtained was dissolved in 100 ml of methanol, and 9.6 ml (4.9 mmol) of a 0.51M sodium methoxide solution in methanol were added to the solution. The resulting mixture was then stirred for 1 hour. At the end of this time, 0.6 ml of acetic acid were added, to terminate the reaction, and then the reaction mixture was freed from the solvent by distillation under reduced pressure . The resulting residue was mixed with water, and the resulting aqueous solution was extracted with a mixture of ethyl acetate and hexane. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate, with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 250 g of silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.39 g of the title compound as an Is oily substance in a 53% yield (total yield of three steps).
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[C:9]([Cl:12])[CH:8]=[C:7]([Cl:13])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:14]1N=CN(C(N2C=NC=C2)=O)C=1>C(O)=O>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[C:10]([OH:11])=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][CH:14]=[N:1]2
Reactant: NC(=O)c1c(Cl)cc(Cl)c(O)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O=CO
Product: O=c1[nH]cnc2c(O)c(Cl)cc(Cl)c12

Procedure:
According to the procedure described in Step C, 2-amino-4,6-dichloro-3-hydroxybenzamide and formic acid in the presence of CDI gave, after washing the crude product with MeOH, 5,7-dichloro-8-hydroxy-3H-quinazolin-4-one as a white solid (36%).—1H NMR (DMSO-d6): δ 8.12 (s, 1H), 7.55 (s, 1H); mass spectrum: m/z 229, 231, 233 (M+−1, 100%, 66%, 11%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:22]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:30][CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: NCCN1CCOCC1
Product: COc1ccc(N(C)c2nc(NCCN3CCOCC3)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (10 mg, 0.033 mmol) and 2-morpholin-4-yl-ethylamine (30 μL) by a procedure similar to Example 10 and was isolated as white powder (10 mg, 100%). 1H NMR (CDCl3): 7.42 (dd, J=8.7 and 1.2 Hz, 1H), 7.36 (ddd, J=8.1, 6.6 and 1.5 Hz, 1H), 7.10-7.09 (m, 2H), 6.92-6.86 (m, 3H), 6.67 (ddd, J=8.1, 6.6 and 1.4 Hz, 1H), 3.82 (s, 3H), 3.75-3.62 (m, 6H), 3.52 (s, 3H), 2.55-2.44 (m, 6H).
Reaction SMILES: [OH:1][C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[C:3]([OH:5])=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[N:34]12[CH2:41][CH2:40][CH:37]([CH2:38][CH2:39]1)[C@@H:36](O)[CH2:35]2>C1COCC1.C(OCC)(=O)C>[N:34]12[CH2:41][CH2:40][CH:37]([CH2:38][CH2:39]1)[C@@H:36]([O:4][C:3](=[O:5])[C:2]([OH:1])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:35]2
Reactant: COc1cccc(C(O)(C(=O)O)c2cccc(OC)c2)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2cccc(OC)c2)c1

Procedure:
To a stirred solution of hydroxy-bis-(3-methoxy-phenyl)-acetic acid (Intermediate J) (1.384 g, 4.8 mmol) in dry THF (2.0 ml) is added CDI (0.870 g, 5.3 mmol) and the mixture is heated to reflux for 90 minutes. (R)-1-aza-bicyclo[2.2.2]octan-3-ol (0.67 g, 5.3 mmol) is then added. After refluxing for 16 hours, the reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is then extracted with 2M HCl and the aqueous portion is treated with potassium carbonate to basify the solution. The aqueous portion is re-extracted with ethyl acetate. The organic portions are combined, dried over MgSO4 and concentrated in vacuo to yield a crude residue which is purified using C-18 reverse phase column chromatography (eluent: water-acetonitrile), to afford the titled compound.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([F:14])=[CH:8][C:5]=1[CH:6]=[O:7]>C(O)C>[F:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([F:14])=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: COc1cc(F)cc(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(F)cc(CO)c1F
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
Sodium borohydride (2.83 g, 74.7 mmol) was added to a stirred solution of 2,5-difluoro-3-methoxybenzaldehyde (8.57 g, 49.8 mmol) in ethanol (100 ml) at room temperature. After 30 min, the mixture was concentrated, the residue was diluted with ether (300 ml) and successively washed with water (200 ml), 10% citric acid (200 ml), water (200 ml), brine (200 ml), and dried over magnesium sulfate. Removal of solvent gave 8.26 g (95%) of the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1cccc(F)c1B(O)O
Product: CCCNC(=O)c1nnc2c(-c3c(F)cccc3OC)cccc2c1N
Yield: 42.5 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-fluoro-6-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were reacted to afford the title compound (73 mg, 42% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (br, 1H), 7.93 (m, 1H), 7.78-7.69 (m, 2H), 7.42-7.31 (m, 1H), 6.89-6.80 (m, 2H), 3.70 (s, 3H), 3.44 (apparent quartet, J=7.0 Hz, 2H), 1.64 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=355 (M+H). HPLC 1.68 min.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)C=C1>>[CH2:6]1[C:1]2[NH:7][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: NNc1ccccc1
Product: c1ccc2c3c([nH]c2c1)CCCC3

Procedure:
In Scheme XVII, Step A, a phenylhydrazine salt (for example the hydrochloride salt) of formula (4), is reacted with a cyclic ketone of formula (3), wherein Z=OBn, in a Fischer indole reaction to provide a tetrahydrocarbazole of formula (5). The hydrazine and ketone are reacted in acetic acid and heated at about 60 to 110° C., for about 4 to 48 hours. The product is isolated by removal of the acetic acid under reduced pressure and trituration of the material in an inert solvent, preferably dichloromethane. After filtration, the filtrate is concentrated and the resulting material purified using standard techniques such as recrystillization or silica gel chromatography.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[C:30]1([S:36]C2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Na]>CN(C)C=O>[CH3:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][CH2:13][C:12]([C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([CH2:2][S:36][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:4][CH:5]=4)=[O:11])=[CH:18][C:17]=3[CH:19]=2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: c1ccc(Sc2ccccc2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccc4)cc2)CCO3)cc1
Yield: 113.9 %

Procedure:
A solution of N-(4-chloromethylphenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15 g) and sodium phenyl sulfide (0.05 g.) in dimethylformamide (10 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7—(4-methylphenyl)-N-(4—(phenyl-thiomethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 82) (0.13 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:30][CH2:31][CH3:32]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([CH2:30][CH2:31][CH3:32])[C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCn1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Temperature: 50 °C
Yield: 65 %

Procedure:
10 Parts of 2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-3H-1,2,4-triazol-3-one are dissolved in 300 parts of dimethyl sulfoxide at 100° C. Then there are added 1.6 parts of sodium hydride dispersion 50% and stirring is continued while the mixture is allowed to cool to about 50° C. 3.9 Parts of 1-bromopropane are added and the whole is stirred overnight at room temperature. The reaction mixture is poured onto water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 2-propanol. The product is filtered off and dried; yielding 7.5 parts (65%) of 2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-2-propyl-3H-1,2,4 -triazol-3-one.