Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].[H-].[Na+].I[CH3:36].O>CN(C=O)C>[C:1]([CH2:4][NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:36])[C:18]([N:20]3[CH2:21][CH2:22][CH:23]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[CH2:24][CH2:25]3)=[O:19])=[CH:15][CH:16]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)CN[C@@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(F)cc4)CC3)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CN[C@@H]1CCN(c2ccc(N(C)C(=O)N3CCC(c4ccc(F)cc4)CC3)cc2)C1
Reaction time: 2 h

Procedure:
(R)-4-(4-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide (22 mg) was added to a suspension of sodium hydride (95% in oil; 0.005 g) in DMF (1 ml). After evolution of gas ceased, iodomethane (0.02 ml) was added. After two hours, the reaction mixture was cautiously hydrolyzed with water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated, and the residue was crystallized from pentane. This resulted in the product with the molecular weight of 452.58 (C26H33FN4O2); MS (ESI): 453 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12](=[O:16])[C:13](O)=[O:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:23]([NH2:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[C:1]([C:5]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:12](=[O:16])[C:13]([NH:25][CH2:23][CH3:24])=[O:14])[CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(F)ccc1OC1CN(C(=O)C(=O)O)C1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CCNC(=O)C(=O)N1CC(Oc2ccc(F)cc2C(C)(C)C)C1
Yield: 46.7 %

Procedure:
To a stirred solution of [3-(2-tert-butyl-4-fluorophenoxy)azetidin-1-yl](oxo)acetic acid (0.27 g, 0.93 mmol) and ethylamine hydrochloride (89 mg, 1.1 mmol) in acetonitrile (20.0 mL) were added EDCI (0.21 g, 1.1 mmol) and HOBt (0.17 g, 1.1 mmol) at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure, the resulting residue was partitioned between ethyl acetate and water and separated. The organic layer was washed with 10% sodium bicarbonate, saturated sodium chloride, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 66:34 to 34:66 hexane/ethyl acetate) to provide 2-[3-(2-tert-butyl-4-fluorophenoxy)azetidin-1-yl]-N-ethyl-2-oxoacetamide (0.14 g, 48%) as a white powder.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.P(Cl)(Cl)([Cl:18])=O.N>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]3[O:13][CH2:14][CH2:1][O:2][C:3]=3[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=c1[nH]cnc2cc3c(cc12)OCCO3
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: Clc1ncnc2cc3c(cc12)OCCO3
Temperature: 0 °C

Procedure:
A mixture of 25.3 g. of 6,7-ethylenedioxyquinazolin-4(3H)-one and 50 ml. of phosphorus oxychloride is refluxed for 10 minutes, cooled, and added with stirring to one liter of ice. After addition of concentrated ammonia the resulting mixture is extracted with chloroform and the chloroform solution chromatographed through 300 mls. of silica gel while eluting with chloroform. Evaporation of the eluent yields 4-chloro-6,7-ethylenedioxyquinazoline, m.p. 169°-174°C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH:13]=2)=[O:10])[C:6]=1[O:7][CH3:8].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]([C:5]2[C:6]([O:7][CH3:8])=[C:2]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)[S:3][CH:4]=2)=[O:10])=[CH:13][C:14]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1
Reactant: COc1ccc(NC(=O)c2csc(Br)c2OC)cc1N1CCN(C)CC1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(NC(=O)c2csc(-c3ccncc3)c2OC)cc1N1CCN(C)CC1

Procedure:
2-Bromo-N-[4-methoxy-3-(4-methyl- 1-piperazinyl)phenyl]-3-methoxythiophene-4-carboxamide (0.20 g;0.45 mmol) was stirred with 4-pyridylboronic acid (0.056 g;0.45 mmol), tetrakis(triphenylphosphine)palladium(0) (0.024 g) and anhydrous sodium carbonate (0.053 g;0.50 mmol) in water (5 ml) and DME (5 ml) and the whole heated at reflux under Ar (18 hours). The reaction mixture was poured into 10% Na2CO3 (aq) (20 ml) and extracted into CHCl3. The organic extracts were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 4%MeOH/CHCl3 to yield a orange gum (0.088;44%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:16])=[O:15])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Cl[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1>C1COCC1>[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[O:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:15])=[O:16])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCO)cc1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCOc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To sodium hydride (26 mg, 55-65% in mineral oil) was added THF (10 ml) followed by the addition of 2-phenyl-ethenesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (100 mg). The mixture was stirred for 1 h at rt. Then 2-chloro-pyrimidine (46 mg) was added and stirring continued for 19 h at 80° C. The solvent was evaporated and diethylether (20 ml) was added to the residue. The precipitate was filtered off and washed with diethylether, dissolved in water and acidified by citric acid. The precipitate was filtered off and the crude material was purified by chromatography over silicagel with hexane/EtOAc=1/1 to give 2-phenyl-ethenesulfonic acid {6-[2-(pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (23.7 mg); tR=4.85 (LC); [M+H]+=490.27 (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:13][C:14]#[N:15]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:7][CH2:13][C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: SCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCSCc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 100 %

Procedure:
13 ml (15.9 g; 0.1 mol) of 4-chlorobenzylmercaptan and a solution of 4.2 g (0.105 mol) of NaOH in 50 ml of water are mixed whilst cold. Thereafter the mixture is heated to about 60° C. and then 7.5 ml (about 1.2 mols) of chloroacetonitrile are added dropwise at this temperature. At the end of this addition (the temperature is then about 80° C.) the mixture is heated under reflux (100° C.) for 30 to 45 minutes. After cooling, the oil which has formed is extracted with ether and the aqueous phase is discarded. The ether solution is washed with dilute NaOH and then with water until the wash waters have a neutral pH. The ether phase is dried over MgSO4 which is filtered off before the ether is evaporated. 19.7 g of the stated product are collected (yield about 100%, relative to the starting 4-chlorobenzylmercaptan); it is in the form of an oil.
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21](OS(C(F)(F)F)(=O)=O)[C:20]=1[N+:33]([O-:35])=[O:34].Cl.[CH3:37][O:38][CH2:39][CH:40]([NH2:42])[CH3:41]>>[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:42][CH:40]([CH3:41])[CH2:39][O:38][CH3:37])[C:20]=1[N+:33]([O-:35])=[O:34]
Reactant: COCC(C)N
Reactant: CN(C)c1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COCC(C)Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-]
Yield: 48.9 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester TFA (1.1 g, 2.49 mmol) and 2-methoxy-1-methyl-ethylamine HCl (208 mg, 1.7 mmol) were treated substantially as described in Part C of Example 19a to produce 318 mg of crude [4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][O:14][C:13]4[CH:16]=[C:17]5[C:21](=[CH:22][C:12]3=4)[CH2:20][CH2:19][O:18]5)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.CC1C2C=[C:30]3[C:35]4(C5C(=CC=CC=5)NC4=O)[CH2:34][O:33][C:31]3=[CH:32]C=2ON=1.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][O:14][C:13]4[CH:16]=[C:17]5[C:21](=[CH:22][C:12]3=4)[CH2:20][CH2:19][O:18]5)[C:7](=[O:11])[N:8]2[CH2:32][C@H:31]2[CH2:30][CH2:35][CH2:34][O:33]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(F)ccc2C12COc1cc3c(cc12)CCO3
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(C[C@H]2CCCO2)c2cc(F)ccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 6′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (47%) as a colorless solid: mp 137-139° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) 7.08-7.03 (m, 1H), 6.88-6.83 (m, 1H), 6.73-6.66 (m, 1H), 6.46 (s, 1H), 6.38 (s, 1H), 4.74 (ABq, 2H), 4.52 (t, J=9.0 Hz, 2H), 4.25-4.20 (m, 1H), 3.96-3.60 (m, 4H), 2.98 (t, J=9.0 Hz, 2H), 2.08-1.86 (m, 3H), 1.73-1.64 (m, 1H); 13C NMR (75 MHz, CDCl3) δ178.0, 161.9, 161.2, 128.1, 124.7, 120.0, 118.8, 109.5, 109.2, 98.8, 98.4, 93.2, 80.6, 72.4, 68.3, 57.3, 44.8, 29.2, 28.9, 25.7; MS (ES+) m/z 382.0 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:12]2[N:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Yield: 8.1 %

Procedure:
The title compound (9.3 mg) was prepared from 164.0 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 63.8 mg of 4-chlorophenylboronic acid as in Example 196. MS (ESI): exact mass calculated for C19H18ClN3, 323.12; found, m/z 324.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.33-7.25 (m, 4H), 7.23-7.16 (m, 3H), 7.09-7.06 (m, 2H), 3.10-3.07 (m, 2H), 3.03-3.00 (m, 2H), 2.99-2.96 (m, 2H), 2.66-2.63 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]#[N:19]>>[CH3:12][N:13]1[C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=2)=[CH:16][CH:15]=[C:14]1[C:18]#[N:19]
Reactant: Cn1cccc1C#N
Reactant: CCC(=O)c1ccc(Br)cc1
Product: CCC(=O)c1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared from 1-(4-bromophenyl)-propan-1-one and 1-methyl-2-cyanopyrrole according to the coupling procedure as described in example 1. MS (ES) m/z 239.2; HRMS: calcd for C15H14N2O+H+, 239.1179; found (ESI, [M+H]+), 239.1193.
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:18][C:19]1[CH:20]=[C:21]([C:26](=[C:31]2[CH2:34][NH:33][CH2:32]2)[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:23]([F:25])[CH:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:2]([N:33]2[CH2:34][C:31](=[C:26]([C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=3)[C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:32]2)[C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(=C1CNC1)c1cc(F)cc(F)c1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1)c1cc(F)cc(F)c1

Procedure:
A mixture of 99 mg (0.32 mmol) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile, 80 mg (0.216 mmol) of 3-[1-(3,5-difluorophenyl)-2,2-dimethylpropylidene]azetidine and 113 uL (0.65 mmol) of N,N-diisopropylethylamine in 3 mL of acetonitrile was heated at reflux for 3 h. Then the reaction was concentrated and the residue was dissolved in 5 ml of hexane/ether. A solution of 1 mL of 1N HCl in ether was added to above solution to make the salt. The mixture was filtered and the solids were washed with hexane/ether. The residue was neutralized with NaOH and the free base was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H-NMR (CDCl3) δ 1.07 (s, 9H), 3.37 (m, 2H), 4.06 (m, 2H), 4.50 (s, 1H), 6.58 (d, J=8 Hz, 2H), 6.74 (m, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.39 (t, J=7.7 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.72 (s, 1H); Mass Spectrum: m/e=463 (M+1 35Cl) and 465 (M+1 37Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:13][NH2:14].[Br:15][C:16]1[S:20][C:19]2=[N:21][C:22]([C:24](O)=[O:25])=[CH:23][N:18]2[CH:17]=1>>[Br:15][C:16]1[S:20][C:19]2=[N:21][C:22]([C:24]([NH:14][CH2:13][C:3]3[CH:4]=[C:5]([O:8][C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:7][C:2]=3[F:1])=[O:25])=[CH:23][N:18]2[CH:17]=1
Reactant: NCc1cc(OC(F)(F)F)ccc1F
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: O=C(NCc1cc(OC(F)(F)F)ccc1F)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (2-fluoro-5-(trifluoromethoxy)phenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51]([C:53]1[S:54][C:55]2[CH2:56][NH:57][CH2:58][CH2:59][C:60]=2[N:61]=1)=[O:52]>CN(C=O)C>[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51]([C:53]1[S:54][C:55]2[CH2:56][N:57]([C:12](=[O:14])[CH2:11][NH:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:58][CH2:59][C:60]=2[N:61]=1)=[O:52]
Reactant: O=C(O)CNc1ccc2c(c1)OCO2
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)CNc1ccc3c(c1)OCO3)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of (Benzo[1,3]dioxol-5-ylamino)-acetic acid. (1.0 mmol) in dry DMF (10 mL), were added 1-hydroxybenzotriazole (1.2 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2 mmol) and N-methylmorpholine (2.0 mmol). Solution was cooled to 0° C. N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide. obtained in step VIII of Example 1 was then added and mixture was stirred at room temperature overnight. Reaction mixture was concentrated, diluted with water, extracted with dichloromethane, washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatograph to obtained the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH:11]([N:14](CC)[CH:15](C)C)(C)C.C(N(CC)CC)C.Cl.CNC>O1CCCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:14]([CH3:15])[CH3:11])[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)cc(N(C)C)n1
Yield: 73.5 %

Procedure:
A mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (5.0 g, 26 mmol), N,N-diisopropylethylamine (3.1 g, 26 mmol), triethylamine (7.15 mL, 51 mmol), and N,N-dimethylamine hydrochloride (2.09 g, 26 mmol) in tetrahydrofuran (50 mL) was heated at reflux for 16 hours. The solvent was removed and the crude material was redissolved in EtOAc and washed with a solution of citric acid (2×100 mL), followed by water (2×100 mL) and brine (2×100 mL). The organic layers were combined, dried over anhydrous MgSO4, concentrated and purified by flash chromatography [eluent: EtOAc/hexane (1:19)], giving the desired product (3.89 g, 73%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1.[CH2:24]([NH2:27])[CH2:25][NH2:26]>C(OCC)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:26][CH2:25][CH2:24][NH2:27])=[CH:3][C:4]([N:13]1[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]1)=[N:5]2
Reactant: Clc1cccc2nc(N3CCCc4ccccc4C3)cc(Cl)c12
Reactant: NCCN
Solvent: CCOC(C)=O
Product: NCCNc1cc(N2CCCc3ccccc3C2)nc2cccc(Cl)c12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The mixture of 2-(4,5-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine prepared above and ethane-1,2-diamine (2 mL) was heated with stirring in a 10 mL microwave process vial for 2 hours at 150° C. under microwave irradiation. The reaction mixture was diluted with ethyl acetate (20 mL), and then washed with water (20 mL). The organic fraction was dried over sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give 20 mg of product as a white powder. MS obsd. (ESI+) [(M+H)+] 367. 1H NMR (400 MHz, CD3OD) δ ppm 7.46-7.42 (m, 2 H), 7.27-7.23 (m, 1 H), 7.16-7.11 (m, 3 H), 7.02 (66, J=7.6, 1.2 Hz, 1 H), 5.97 (s, 1 H), 4.79 (s, 2 H), 4.13 (brs, 2 H), 3.38-3.21 (m, 2 H), 3.04-3.02 (m, 2 H), 2.96 (t, J=6.0 Hz, 2 H), 1.91-1.86 (m, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)[CH3:2].[N:15]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][NH2:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCc1cccc(NN)c1
Reaction time: 1 h

Procedure:
To a solution of 3-(3-amino-phenyl)-propionic acid ethyl ester (14 g, 72.5 mmol) in concentrated HCl (200 mL) was added an aqueous solution (10 mL) of NaNO2 (5 g, 72.5 mmol) at 0° C. and the resulting mixture was stirred for 1 h. A solution of SnCl2.2H2O (33 g, 145-mmol) in concentrated HCl (150 mL) was then added at 0° C. The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with ethanol and ether to give 3-(3-hydrazino-phenyl)-propionic acid ethyl ester as a white solid, which was used without further purification.
Reaction SMILES: C1C2C(=CC=CC=2)CC1C(O)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C[O:27][C:28]([CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[S:39](Cl)(=[O:41])=[O:40])[CH2:31]1)=[O:29]>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][N:23]([S:39]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:37]=3[CH2:38][CH:30]([C:28]([OH:29])=[O:27])[CH2:31]4)(=[O:41])=[O:40])[CH2:22][CH2:21]2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Agent: O=C(O)C1Cc2ccccc2C1
Product: O=C(O)C1Cc2cccc(S(=O)(=O)N3CCN(c4ccc(Cl)cc4)CC3)c2C1

Procedure:
4-|4-(4-Chloro-phenyl)-piperazine-1-sulfonyl|-indan-2-carboxylic acid. The compound 4-[4-(4-chloro-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 1-(4-chloro-phenyl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): δ 7.58 (d, 1H), 7.56 (d, 1H), 7.43 (t, 1H), 7.23 (d, 2H), 6.92 (d, 2H), 3.50-3.41 (m, 2H), 3.40-3.29 (m, 1H), 3.28-3.13 (m, 6H), 3.12-3.04 (m, 4H); MS (ESI): 420.9 (M+H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:3]([O:4][CH3:5])[CH3:2])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (5.5 g, 56.4 mmol) was added to a suspension of 4-iodobenzoyl chloride (10.0 g, 37.5 mmol) and toluene (60 mL) at 0° C. After 10 min, a solution of sodium carbonate (16.0 g, 151 mmol) and water (250 mL) was added over 50 min via addition funnel. With vigorous stirring, the reaction was maintained at 0° C. for 2 h and then partitioned. The toluene layer was washed with water (125 mL), washed with brine (125 mL), and then concentrated. The residue was redissolved in toluene and filtered to remove trace solids. This solution was concentrated to give 10.5 g of 4-iodo-N-methoxy-N-methylbenzamide as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.83 (d, 2H), 7.32 (d, 2H), 3.53 (s, 3H), 3.25 (s, 3H); LCMS: 292.4 (M+H)+. Step 2: 1-(4-Iodophenyl)-2-(4-methoxyphenyl)ethanone
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1Br.C([Mg]Cl)(C)C.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][CH:6]=1
Reactant: COC(=O)c1cc(Br)c(Br)o1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a solution of methyl 4,5-dibromo-2-furancarboxylate (3.3 g, 11.62 mmol) in tetrahydrofuran (46 ml) at −40° C. was added isopropylmagnesium chloride (6.97 ml, 13.95 mmol). After 1 h, Water (11 ml) was added and the solution warmed to 25° C. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (3% EtOAc in hexanes) affording methyl 4-bromo-2-furancarboxylate (1.4 g, 6.49 mmol, 56% yield) as a yellow solid: LCMS (ES) m/e 205, 207 (M, M+2)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH3:24])[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][CH:22]=[CH:23][C:16]=23)[CH2:9]1)C1C=CC=CC=1.C(O)C.[ClH:28]>O.[OH-].[Pd+2].[OH-]>[ClH:28].[ClH:28].[ClH:28].[CH3:24][N:14]([CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:21][CH:22]=[CH:23][C:16]=12
Reactant: CN(c1ccnc2[nH]ccc12)C1CCCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(c1ccnc2[nH]ccc12)C1CCCNC1
Reaction time: 60 h

Procedure:
A degassed mixture of N-(1-benzylpiperidin-3-yl)-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine (0.17 g, 0.00053 mol) and palladium hydroxide (0.15 g, 0.00011 mol) in ethanol (3.5 mL, 0.060 mol) and 3.0 M of hydrogen chloride in water (0.40 mL) was stirred under an atmosphere of hydrogen over 2.5 days. The reaction mixture was filtered and washed with MeOH. The filtrate was concentrated under vacuum to give 92 mg of orange oil.