Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[O:11].Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:10]([NH:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:11])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 80.2 %

Procedure:
2-Methoxyphenyl isocyanate (0.4 g, 2.6 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and triethylamine (0.3 g, 2.8 mmol) in THF (30 mL) at 5-10° C. After stirring for 10 minutes at 5° C., the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL) for 30 minutes. The solid was collected and slurried with hot methanol (15 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(2-methoxy-phenyl)-urea (0.7 g, 80%) as a white solid: mp 214-216° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 3.83 (s, 3H, OCH3), 4.73 (d, J=5.7 Hz, 2H, CH2), 5.13-5.20 (dd, J=5.3 and 12.5 Hz, 1H, CH), 6.79-6.98 (m, 3H, Ar), 7.49 (t, H=5.7 Hz, 1H, NH), 7.77-7.89 (m, 3H, Ar), 8.04-8.08 (dd, J=1.4 and 7.3 Hz, 1H, Ar), 8.19 (s, 1H, NH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 48.86, 55.64, 110.59, 118.07, 120.42, 121.22, 121.88, 127.16, 129.20, 131.61, 133.65, 134.77, 140.112, 147.40, 155.24, 167.00, 167.50, 169.83, 172.76; Anal. calcd. for C22H20N4O6+0.66H2O: C, 58.94; H, 4.79; N, 12.50. Found: C, 59.24; H, 4.86; N, 12.74.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH:11]([CH2:15][CH2:16][OH:17])[CH2:10]2)[N:3]=1.[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=2[F:37])=[CH:22][C:23]=1[C:24]([NH2:26])=[O:25]>>[F:37][C:28]1[CH:29]=[C:30]([C:33]([OH:36])([CH3:34])[CH3:35])[CH:31]=[CH:32][C:27]=1[C:21]1[S:20][C:19]([NH:18][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH:11]([CH2:15][CH2:16][OH:17])[CH2:10]3)[N:3]=2)=[C:23]([C:24]([NH2:26])=[O:25])[CH:22]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OCCC1CN(Cc2nccc(Cl)n2)CCO1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccnc(CN4CCOC(CCO)C4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 106, Step 2 with 2-{4-[(4-chloropyrimidin-2-yl)methyl]morpholin-2-yl}ethanol (50 mg, 0.19 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (57 mg, 0.19 mmol) as starting materials.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15]C(=O)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(O)C>[CH2:26]([O:25][C:21]1([O:22][CH2:23][CH3:24])[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15]1)[CH3:27]
Reactant: CCOC(OCC)OCC
Reactant: O=C1CCC(CCOCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC1(OCC)CCC(CCOCc2ccccc2)CC1

Procedure:
4-(2-benzyloxyethyl)cyclohexanone (133.0 g, 0.57 mol) is dissolved in ethanol (1200 mL), and then triethylorthoformate (296 mL) and p-toluenesulfonic acid monohydrate (10.9 g, 0.057 mol) are added. The resulting mixture is stirred and refluxed for 2 hours. After addition of triethylamine (8.8 mL, 0.063 mol) at room temperature, the mixture is concentrated. After addition of sat. NaHCO3 aq. (500 mL), the resulting mixture is extracted with EtOAc (1000 mL). The water layer is extracted with EtOAc (1000 mL×2) and the combined organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude mixture is purified by short pad silica gel column chromatography to afford [2-(4,4-diethoxycyclohexyl)ethoxymethyl]benzene as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.[CH2:17]([O:19][C:20]([C:22]1[C:23](=[O:45])[C:24]2[CH:29]=[N:28][C:27](S(C)(=O)=O)=[N:26][C:25]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39]3)[CH:35]=1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[C:23](=[O:45])[C:24]2[CH:29]=[N:28][C:27]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:15][CH:14]=3)=[N:26][C:25]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39]3)[CH:35]=1)=[O:21])[CH3:18]
Reactant: CN1CCN(CCc2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCN(C)CC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamine (53 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a yellow solid (70 mg, 53%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.28 (s, 1H), 8.46 (s, 1H), 7.60 (br, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.21 (s, 1H), 7.16 (br, 2H), 7.12 (d, J=7.9 Hz, 1H), 6.86 (br, 2H), 4.30 (q, J=7.1 Hz, 2H), 2.99 (t, J=7.4 Hz, 2H), 2.93 (t, J=7.4 Hz, 2H), 2.64 (n, 2H), 2.47 (m, 10H), 2.34 (s, 3H), 2.16 (m, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][O:16][CH2:17]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:32](=[O:38])OC(Cl)(Cl)Cl)Cl.[NH2:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][OH:46])=[CH:43][CH:42]=1>>[OH:46][CH2:45][C:44]1[CH:47]=[CH:48][C:41]([NH:40][C:32]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([N:13]4[CH:14]5[CH2:20][CH2:19][CH:18]4[CH2:17][O:16][CH2:15]5)[N:10]=3)=[CH:22][CH:23]=2)=[O:38])=[CH:42][CH:43]=1
Reactant: Nc1ccc(CO)cc1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: O=C(Nc1ccc(CO)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Yield: 30.9 %

Procedure:
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-aminobenzyl alcohol (22 mg, 0.18 mmol) gave the title compound as off-white solid (9.6 mg, 31% yield). MS (ESI) m/z 518.5.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=2)[O:7][CH2:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccccc1COc1cccc(CCO)c1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
Methyl 2-{[3-(2-hydroxyethyl)phenoxy]methyl}benzoate (0.5 g, 1.75 mmol), 4-(benzyloxy)phenol (0.35 g, 1.75 mmol) and triphenylphosphine (0.5 g, 1.92 mmol) were added to a dry roundbottomed flask and fitted with a septum Dry toluene (10 ml) was added and N2 was flushed through the mixture for 5 minutes. Diisopropyl (E)-diazene-1,2-dicarboxylate (0.39 g, 1.92 mmol) was added dropwise and the solution was stirred at room temperature. After three hour, another equivalent of reagents was added and stirred for one hour. After removing the solvent by evaporation the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 0.319 g methyl 2-[(3-{2-[4-(benzyloxy)phenoxy]ethyl}phenoxy)methyl]benzoate (yield 39%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:40]=[CH:39][C:29]2=[N:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37](=[O:38])[N:28]2[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:40]=[CH:39][C:29]5=[N:30][C:31]6[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=6[C:37](=[O:38])[N:28]5[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: O=c1c2ccccc2nc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5nc6ccccc6c(=O)n5n4)cc3CC[C@@H]12
Yield: 59.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-10H-pyridazino[6,1-b]quinazolin-10-one (107 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0-10% methanol/ethyl acetate eluent gradient) to give 103 mg (62%) of the title compound as an amorphous foam. mp 110-114°. FDMS: m/e=456. α[D]589 =+54.77 (c=0.49, chloroform).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:13]([C:21](OC)=[O:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:2].[H][H]>C(O)C.[Ni]>[O:22]=[C:21]1[CH:13]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:4]2[N:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=2[CH2:1][NH:2]1
Reactant: COC(=O)C(C(=O)OC(C)(C)C)c1ncc(C(F)(F)F)cc1C#N
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1C(=O)NCc2cc(C(F)(F)F)cnc21
Yield: 99.4 %

Procedure:
To a solution of tert-butyl methyl [3-cyano-5-(trifluoromethyl)pyridin-2-yl]malonate (4.02 g, 11.7 mmol) in ethanol (60 mL) was added a slurry of Raney Nickel (0.60 g, 10 mmol). The mixture was placed on a Parr apparatus and hydrogenated under hydrogen at 40 psi overnight. The suspension was filtered through celite and the filtrate was evaporated in vaccuo to afford 3.68 g (99.6%) of the desired product as a yellow oil. LC-MS calculated for C14H15F3N2O3: (M+H)+317; found 217.1 (M−CO2tBu+H+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:32][C@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C=O.F[C:46](F)(F)C(O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)[CH:15]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:46][N:32]1[C@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])=[O:42]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)C(=O)OC)c1ccccc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Temperature: 0 °C

Procedure:
(S)-3-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (0.2 g) was dissolved in 8 mL dry dioxane and cooled to 0° C.; paraformaldehyde (50 mg) and 2 mL trifluoroacetic acid were added. The reaction was stirred for 12 hours at room temperature and neutralized to pH 7 with aqueous NaHCO3, then the mixture was extracted with EtOAc. The organic extract was washed with water and brine, and then dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc) to get (3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (0.14 g). LCMS (m/z): 619.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>>[CH3:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[C:21]=1[C:27]1[CH:28]=[CH:29][C:30]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)=[O:18])=[O:7])=[CH:31][CH:32]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCCc2ccc(O)cc2)N(C(=O)c2ccc(-c3c(C)cccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and 4-(2-aminoethyl)phenol, the title compound was obtained in 87% purity by HPLC. MS(ESI+): m/z=486.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:23](OCC)=[O:24])[N:6]2C.[ClH:28].[NH2:29][C:30]([NH2:32])=[NH:31].[CH3:33][O-].[Na+]>CO>[ClH:1].[ClH:28].[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:23]([N:31]=[C:30]([NH2:32])[NH:29][CH3:33])=[O:24])[NH:6]2
Reactant: C[O-]
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cc2c(Cl)cc(Oc3ccc(CN(C)C)cc3)cc2n1C
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2c(Cl)cc(Oc3ccc(CN(C)C)cc3)cc2[nH]1
Yield: 129.7 %

Procedure:
The reaction was carried out in a manner similar to Example 186 b) except for using 0.29 g (0.75 mmol) of ethyl 4-chloro-6-[4-(dimethylaminomethyl)-phenoxy]-1-methyl-2-indolecarboxylate, 1.43 g (15.0 mmol) of guanidine hydrochloride, 0.81 g (15.0 mmol) of sodium methoxide and 30 ml of methanol. Thus, 0.23 g (66.0%) of 4-chloro-6-[4-(dimethylaminomethyl)phenoxy]-1-methyl-2-indoloylguanidine dihydrochloride was obtained.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:42][O:43][CH2:44][C:45]1[O:46][CH:47]=[C:48]([CH2:50][N:51]2[N:55]=[C:54]([NH2:56])[CH:53]=[N:52]2)[N:49]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:42][O:43][CH2:44][C:45]1[O:46][CH:47]=[C:48]([CH2:50][N:51]2[N:55]=[C:54]([NH:56][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:53]=[N:52]2)[N:49]=1
Reactant: COCc1nc(Cn2ncc(N)n2)co1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCc1nc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)co1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990, p. 112) (14 mg, 0.06 mmol) in CH2Cl2 (0.3 mL) was treated at rt with DMAP (2 mg, 0.02 mmol), HOBt (10 mg, 0.08 mmol), EDC (31 mg, 0.16 mmol) and DIPEA (0.04 mL, 0.26 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((2-(methoxymethyl)oxazol-4-yl)methyl)-2H-1,2,3-triazol-4-amine (13 mg, 0.06 mmol) in CH2Cl2 (0.3 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (5 mL), the org. phase was washed with water (5 mL), dried over Na2SO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (1:2 hept-EA) gave the title compound as a colorless oil: TLC: rf (1:2 hept-EA)=0.36. LC-MS-conditions 07: tR=0.88 min, [M+H]+=408.69.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]1[C:23](=[O:29])[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1>CN(C=O)C.C(Cl)Cl>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:21][C:22]2[C:23](=[O:29])[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: Cn1cccc(CBr)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)c1=O
Reaction time: 8 h
Yield: 50.6 %

Procedure:
3-Iodo-4-nitro-1H-indazole (0.38 g, 1.3 mmol) was reacted with K2CO3 (0.36 g, 2.6 mmol) in DMF (4 mL) for 15 minutes. 3-(Bromomethyl)-1-methylpyridin-2(1H)-one (0.28 g, 1.4 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with CH2Cl2 (30 mL), filtered and concentrated. The residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated. The residue was suspended in EtOAc (8 mL), stirred for 20 minutes and then filtered to provide 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one (0.27 g, 50% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9](O)[C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(Cl)(Cl)Cl>O>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc2c(c1)C(O)Cc1c(Cl)cccc1S2
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOc1ccc2c(c1)CCc1c(Cl)cccc1S2
Temperature: 25 °C
Yield: 49.9 %

Procedure:
The mixture of 1.1 g of 9-chloro-10,11-dihydro-2-ethoxy-11-hydroxydibenzo[b,f]thiepin and 33 ml of thionyl chloride was refluxed for 3 hrs. and evaporated to obtain the residue, to which was added 50 g of ice-water. The resulting mixture was extracted with chloroform and the extract was washed with water and dried over calcium chloride. The solvent was evaporated to obtain the concentrated which was added with stirring at room temperature to a mixutre of 70 ml of anhydrous tetrahydrofuran and 400 mg of lithium aluminum hydride. The thus obtained mixture was refluxed with stirring for 4 hrs., to which was added 30% sodium hydroxide solution with stirring under cooling with a mixture of ice and sodium chloride. The mixture was filtered and the filtrate was evaporated to obtain the residue, to which was added 100 ml of chloroform and 100 ml of water, and the chloroform layer was collected. This was washed with water, dried and the solvent was evaporated to obtain 520 mg of 9-chloro-10,11-dihydro-2-ethoxydibenzo[b,f]thiepin as oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[Al+3].[Cl-].[Cl-].[Cl-].ClC[CH2:17][C:18](Cl)=[O:19].Cl[CH2:22][Cl:23]>>[Cl:23][CH2:22][C:18](=[O:19])[CH2:17][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:9][CH3:10])[CH:5]=1
Reactant: ClCCl
Reactant: COc1ccccc1OC
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(CC(=O)CCl)cc1OC
Yield: 90 %

Procedure:
To the solution of 1,2-dimethoxybenzene (0.05 mol) dissolved in dichloromethane (30 mL), AlCl3 (0.10 mol) is added batch by batch and 3-chloropropionyl chloride (0.055 mol) is added dropwise, while the internal temperature is maintained below 5° C. Following procedures described in General Method One-Method A, 3-chloro-1-(3,4-dimethoxyphenyl)-propanone is obtained as a white solid (10.3 g). The yield is 90.0%. MS(m/z): 229.0 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].C(N([CH2:11][CH3:12])CC)C.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C(Cl)(Cl)Cl>[CH3:1][N:2]([C:14]([O:16][CH2:17][C:12]1[CH:11]=[CH:20][CH:19]=[CH:18][CH:23]=1)=[O:15])[CH2:3][CH2:4][NH:5][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCCN
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(CCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a stirred solution of N-Methyl-1,2 diaminoethane (7.4 gm) and triethylamine (20.2 gm) in chloroform (50 ml) at 0° was added dropwise over 30 minutes benzyl chloroformate (34.1 gm). The mixture was then left to warm to room temperature over one hour. The organic solution was then washed with water, citric acid solution, sodium bicarbonate solution and finally water again. The chloroform solution was dried over magnesium sulphate and evaporated to give a yellow oil (29.6 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([N:10]=[CH:11][C:12]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([NH:25][C:26]([C:28]4[CH:29]=[CH:30][C:31]5[S:36][CH2:35][C:34](=[O:37])[NH:33][C:32]=5[CH:38]=4)=[O:27])[CH2:21][CH2:20]3)=[N:13]2)=[CH:8][CH:7]=1.C(N(CC)CC)C>CN(C)C=O>[O:37]=[C:34]1[NH:33][C:32]2[CH:38]=[C:28]([C:26]([NH:25][CH:22]3[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][O:16][C:12]4[CH:11]=[N:10][C:9]5[C:14]([N:13]=4)=[CH:15][C:6]([O:5][C:1](=[O:3])[CH3:2])=[CH:7][CH:8]=5)[CH2:20][CH2:21]3)=[O:27])[CH:29]=[CH:30][C:31]=2[S:36][CH2:35]1
Reactant: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Acetyl chloride (11.4 μL, 0.16 mmol, 1.1 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (70 mg, 0.15 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by triethylamine (40.7 μL, 0.29 mmol, 2.0 eq). After 1 hour stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford acetic acid 3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-yl ester as a white powder (35 mg, 41% yield).