Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH:19][S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(=O)(=O)c3ccccc3)c1)N2
Yield: 59 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (135 mg, 0.5 mmol) in dichloromethane (3 mL) was added pyridine (60 mg, 0.75 mmol) in dichloromethane (2 mL) and benzenesulfonylchloride (108 mg, 0.56 mmol) under nitrogen. The resultant mixture was stirred for 20 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether:ethyl acetate=15:1) to afford 120 mg of N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide as yellow solid (Yield: 59%). MS (ESI+APCI) M+1=407.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12]C(C)(C)C)=[O:11])=[CH:6][C:5]([Cl:19])=[CH:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]([O:8][C:9]([CH3:17])([CH3:18])[C:10]([OH:12])=[O:11])=[CH:6][C:5]([Cl:19])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cc(Cl)cnc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1cc(Cl)cnc1Cl)C(=O)O
Reaction time: 8 h
Yield: 125.5 %

Procedure:
To a dichloromethane solution (157 ml) of tert-butyl 2-[(2,5-dichloropyridin-3-yl)oxy]-2-methylpropionate (79.1 g) was added at 0° C. trifluoroacetic acid (157 ml). The reaction solution was brought back to room temperature, stirred overnight, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was azeotroped with toluene to afford 2-[(2,5-dichloropyridin-3-yl)oxy]-2-methylpropionic acid (81.1 g).
Reaction SMILES: [Li+:1].[OH-].C([O:5][C:6]([C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][N:12]=1)=[O:7])C>C1COCC1.CO.O>[Li+:1].[C:13]1([C:10]2[O:9][C:8]([C:6]([O-:7])=[O:5])=[N:12][N:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1nnc(-c2ccccc2)o1
Reaction time: 1 h

Procedure:
LiOH (25 mg, 0.60 mmol) was added at room temperature to a stirred solution of 5-phenyl-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester (60 mg, 0.275 mmol) in THF:MeOH:H2O (3:1:1, 5 mL) and the resulting mixture stirred for 1 hr. Removal of the volatiles by evaporation under reduced pressure afforded 5-phenyl-[1,3,4]oxadiazole-2-carboxylic acid lithium salt, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:19])[CH2:11][NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:6][CH:5]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C1CCN2C(=NCCC2)CC1>>[CH3:17][CH:16]([S:13]([NH:12][CH2:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:9][CH:8]=1)[CH3:19])(=[O:15])=[O:14])[CH3:18]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(CCN)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(CCNS(C)(=O)=O)cc1
Yield: 78.1 %

Procedure:
Scheme Va, step C: {2-[4-(2-Aminoethyl)phenyl]propyl}[(methylethyl)sulfonyl]amine (0.15 g, 0.53 mmol), methanesulfonyl chloride (0.1 mL, 0.58 mmol) and DBU (0.1 mL, 0.61 mmol) were combined and sulfonylation was carried out in a manner analogous to the procedure described in example 2 to provide the final title compound, [(methylethyl)sulfonyl][2-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)propyl]amine, (0.15 g, 78%) as a white crystalline solid. Electron spray M.S. 363 (M*+H). Analysis for C15H26N2O4S2:
Reaction SMILES: NN.[CH3:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:14][N:15]1[C:20]2[N:21]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[S:23][C:19]=2[C:18](=[O:30])[N:17]=[C:16]1[CH2:31][N:32]1C(=O)C2C(=CC=CC=2)C1=O>CO>[NH2:32][CH2:31][C:16]1[N:15]([CH2:14][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:11])([F:13])[F:12])[C:4]=2[CH3:3])[C:20]2[N:21]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[S:23][C:19]=2[C:18](=[O:30])[N:17]=1
Reactant: Cc1c(Cn2c(CN3C(=O)c4ccccc4C3=O)nc(=O)c3sc(N4CCOCC4)nc32)cccc1C(F)(F)F
Agent: NN
Solvent: CO
Product: Cc1c(Cn2c(CN)nc(=O)c3sc(N4CCOCC4)nc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
Hydrazine (3.31 μL, 0.105 mmol) was added to a solution of 2-{[4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-2-(4-morpholinyl)-7-oxo-4,7-dihydro[1,3]thiazolo[4,5-d]pyrimidin-5-yl]methyl}-1H-isoindole-1,3(2H)-dione (60 mg, 0.105 mmol) in Methanol (2 mL). The mixture was stirred at RT for 2 hours. The solvent was removed and the residue was purified by reverse phase HPLC (10% org˜50% org) to give the titled product 16 mg (35%). LC/MS (ES) m/z 440.1 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.30 (br, s, 2H), 7.67 (m, 1H), 7.38 (m, 1H), 6.87 (m, 1H), 5.58 (s, 2H), 4.20 (m, 2H), 3.66 (m, 4H), 3.56 (m, 4H), 2.37 (s, 3H)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[OH-].[Na+].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1ccccc1O
Reactant: BrCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccccc1OCCCCBr

Procedure:
The solution of 19.04 ml of 2-ethylphenol in 24 ml of 1,4-dibromobutane is heated to 100° C. with stirring and admixed slowly with 99.2 ml of 1.6M NaOH. The emulsion is stirred at 100° C. over 20 h. The reaction mixture is cooled and extracted with tert-butyl methyl ether (2×150 ml). The organic phases are washed successively with 2M NaOH (1×150 ml), water (1×150 ml) and brine (1×150 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of distillation. b.p. 132° C. (1.1 mbar); Rt=5.75.
Reaction SMILES: C(O[C:4](=O)[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C([O-])(=O)C.[Na+].[C:24]([O:27][C:28](=O)C)(=[O:26])[CH3:25]>O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[C:28]([O:27][C:24](=[O:26])[CH3:25])[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(OC(C)=O)c2ccccc2c1
Temperature: 25 °C

Procedure:
To a solution of 24 g of 2-Benzylidene-malonic acid diethyl ester in 60 ml of acetic acid anhydride, 7.5 g sodium acetate was added and the reaction mixture was heated to reflux for 5 h. After cooling to RT the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed three times with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C:10]([OH:20])([CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:11][C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1C=CC=CC=1.[Si](C=[N+]=[N-])(C)(C)C>CO>[OH:20][C@:10]([CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])([CH2:11][C:12]([O:14][CH3:22])=[O:13])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:21]
Reactant: CC(C)=CCC(O)(CC(=O)O)C(=O)OCc1ccccc1
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C[C@](O)(CC=C(C)C)C(=O)OCc1ccccc1
Yield: 100 %

Procedure:
To a solution of acid 75 (175.2 mg, 0.599 mmol, 1.00 equiv) in 7:2 PhH:MeOH (6.0 mL) was added a 2.0 M solution of TMSCHN2 (449 μL, 0.899 mmol, 1.50 equiv.). After the resulting gas evolution had subsided, the solvent was removed by rotary evaporation to yield methyl ester 77 (183.7 mg, 100%) as a clear, colorless oil. Rf=0.55 (2:1 hex:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.36 (m, 5H, aryl H), 5.23 (d, 1H, J=12.1 Hz, PhCH2), 5.19 (d, 1H, J=12.1 Hz, PhCH2), 5.08 (m, 1H, vinyl H), 3.68 (s, 1H, OH), 3.62 (s, 3H, OCH3), 2.95 (d, 1H, J=16.2 Hz, C(O)CH2), 2.72 (d, 1H, J=16.3 Hz, C(O)CH2), 2.41 (m, 2H, CHCH2), 1.67 (s, 3H, C(CH3)2), 1.54 (s, 3H, C(CH3)2); 13C NMR (125 MHz, CDCl3) δ 174.84, 171.43, 136.54, 135.46, 128.70, 128.66, 128.60, 116.75, 75.65, 67.79, 51.93, 42.81, 38.11, 26.06, 18.09; IR (neat film) 3514 (m), 3034 (w), 2955 (m), 1742 (s), 1498 (w), 1439 (s), 753 (m), 699 (m) cm−1; LRMS (ESI) calc'd for C17H22O5Na (M+Na+) 329.2, found 329.1.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[CH:9]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=O)(C)(C)C.Cl.O1C2C=CC(CCN)=CC=2OC1.BrC1C=CC(CC(O)=O)=CC=1.O=P(Cl)(Cl)Cl>CN(C=O)C.C(#N)C.C(N(CC)CC)C>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:9]2[C:10]3[CH:11]=[C:12]4[O:20][CH2:19][O:18][C:13]4=[CH:14][C:15]=3[CH2:16][CH2:17][N:8]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2C1Cc1ccc(Br)cc1)OCO3
Agent: Cl
Agent: NCCc1ccc2c(c1)OCO2
Agent: O=C(O)Cc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC#N
Product: Brc1ccc(CC2=NCCc3cc4c(cc32)OCO4)cc1

Procedure:
The synthesis of N-(2-Benzo[1,3]dioxol-5-yl-ethyl)-2-(4-bromophenyl)acetamide 35, 5-(4-bromobenzyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline oxalate salt 37, and 5-(4-Bromobenzyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinoline-6-carboxylic acid tert-butyl ester 38 is shown in scheme-10. Compound 35 was synthesized by coupling of 2-Benzo[1,3]dioxol-5-yl-ethylamine hydrochloride salt 33 with 4-bromophenyl acetic acid 34 using diethyl cyanophosphonate in the presence of triethyl amine in DMF. The amide 35 was cyclized by Bischler Napieralski reaction using POCl3 in anhydrous acetonitrile to get 5-(4-bromobenzyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline 36 which was reduced by NaBH4 and converted to an oxalate salt 37 using oxalic acid dihydrate in methanol. The compound 37 was treated with 1N NaOH in dichloromethane to obtain free amine and this amine was protected with di-tert-butyl dicarbonate in the presence of 1N NaOH in THF to afford compound 38.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][O:48][CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>O1CCCC1>[CH3:47][O:48][CH2:49][C:50]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:51]
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.125 g, 0.207 mmol), in tetrahydrofuran (5 mL), were added, 2-methoxy acetyl chloride (0.034 g, 0.315 mmol, 0.025 mL) and triethylamine (0.107 g, 1.06 mmol, 0.147 mL). The reaction mixture was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was dissolved in 10 mL of ethyl acetate and was washed 3 times with water (5 mL). The crude was used without further purification (0.141 g, 99% yield): ES-MS (m/z) 675 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6](C)[C:7](=[O:29])[CH:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([CH2:27][CH3:28])[CH:20]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C>C1(OC)C=CC=CC=1.C(#N)C.O>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7](=[O:29])[CH:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([CH2:27][CH3:28])[CH:20]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CCc1ccc(CC2N=C(c3ccc(F)cc3)c3cc(Cl)ccc3N(C)C2=O)cc1CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1ccc(CC2N=C(c3ccc(F)cc3)c3cc(Cl)ccc3NC2=O)cc1CC
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (Z)-7-chloro-3-(3,4-diethylbenzyl)-5-(4-fluorophenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (0.1 g, 0.18 mmol) in anisole (3 mL) was added aluminum chloride (0.144 g, 1.08 mmol). The mixture was heated at 85° C. for 1 hour, cooled to ambient temperature and poured into a mixture of ice/water (10 mL) and ethyl acetate (20 mL) and stirred vigorously for 10 min. The layers were separated and the organic phase was dried over sodium sulfate, filtered, and then concentrated. The residue was purified by chromatography (silica gel, 95:5 CH2Cl2:MeOH) to provide an oil which was dissolved in a mixture of acetonitrile (3 mL) and water (1 mL). This solution was freeze-dried overnight to give (Z)-7-chloro-3-(3,4-diethylbenzyl)-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one as an off-white solid: mp 88-90° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.64 (dd, J=8.8, 2.5 Hz, 1H), 7.49 (t, J=5.6 Hz, 2H), 7.30-7.23 (m, 4H), 7.13-7.01 (m, 3H), 3.65 (t, J=5.5 Hz, 1H), 3.32-3.31 (m, 2H), 2.56 (quintet, J=7.3 Hz, 4H), 1.13 (q, J=7.2 Hz, 6H); APCI MS m/z 435 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([NH2:1])[C:3]=1[F:11]
Reactant: Nc1cccc(C(=O)O)c1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(N)c1F
Temperature: 25 °C

Procedure:
To a stirred solution of 3-amino-2-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropewise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-2-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9. A mixture solution of 3-amino-2-fluoro-benzoic acid methyl ester (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-2-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+] 336.0 & 338.0.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[N:7]1)C.O.[NH2:13][NH2:14]>C(O)C>[N:6]1([CH2:5][C:4]([NH:13][NH2:14])=[O:11])[CH:10]=[CH:9][N:8]=[N:7]1
Reactant: NN
Reactant: CCOC(=O)Cn1ccnn1
Solvent: O
Solvent: CCO
Product: NNC(=O)Cn1ccnn1
Temperature: 4 °C
Yield: 73 %

Procedure:
As described for example 112a, [1,2,3]triazol-1-yl-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture heated under reflux for 3 h. The mixture was cooled to 4° C. and the precipitated product was filtered off and dried to afford the title compound as a white solid (yield: 73%). MS: m/e=141.2[M]+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].O.Br[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[NH:8][N:7]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:2]([CH3:3])[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[NH:8][N:7]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1cnc2[nH]nc(Br)c2c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)c1n[nH]c2ncc([N+](=O)[O-])cc12
Reaction time: 15 h
Yield: 22 %

Procedure:
40% Dimethyl amine in water (2.6 mL, 21 mmol) was added to a solution of 3-bromo-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.063 g, 0.26 mmol) in DMF (6.0 mL), and the mixture was placed in a microwave reactor at 140° C. for 15 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and the organic layer was washed with water (3×50 mL). The organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1) to give N,N-dimethyl-5-nitro-1H-pyrazolo[3,4-b]pyridin-3-amine (0.012 g, 22%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=1)=[O:8].[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:25][CH2:24][CH2:23][O:22][CH3:21])[N:14]=1)=[O:8]
Reactant: COCCN
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Solvent: CN1CCCC1=O
Product: COCCNCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Temperature: 80 °C

Procedure:
1-(4-Chloromethyl-thiazol-2-yl)-3-(3,4-dichloro-benzyl)-urea (Intermediate 2, 1 eq.) was taken up in NMP (0.3 M) and methoxyethylamine (2.2 eq.) was added. The reaction was heated overnight at 80° C. An aqueous workup was performed. The crude title compound was purified by column chromatography using 0-8% gradient of 7 N ammonia/MeOH and DCM.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:11]=[C:10]([CH3:12])[C:9]([Br:13])=[CH:8][CH:7]=1.[ClH:14]>>[Br:13][C:9]1[C:10]([CH3:12])=[N:11][C:6]([Cl:14])=[CH:7][CH:8]=1
Reactant: Cc1nc(N)ccc1Br
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1nc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium nitrite (4.5 g, 66 mmol) was added slowly to a solution of 6-amino-3-bromo-2-methylpyridine (3.07 g, 16.4 mmol) in concentrated HCl (40 mL) at −20° C. After 1 h, the reaction was allowed to warm to room temperature and stirred overnight. The reaction was carefully neutralized with ice-cold 5N NaOH until pH=11. The aqueous layer was extracted with Et2O (3×75 mL). The combined organic layers were washed with brine (1×75 mL), dried (Na2SO4) and concentrated in vacuo to afford 3-bromo-6-chloro-2-methylpyridine, as a white solid, which was used in the next step without further purification. LCMS calc.=205.9; found=206.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J=8.2 Hz, 1H); 7.07 (d, J=8.1 Hz, 1H); 2.66 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1.CC(O)C>O>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: CN1CCNCC1
Solvent: CC(C)O
Solvent: O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 102 °C
Yield: 86.5 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (100 g, 0.38 mol), N-methylpiperazine (250 mL, 2.5 vol) and 2-propanol (200 mL, 2 vol) were charged into a three-necked round bottom flask equipped with reflux condenser, overhead stirrer, and thermometer. The reaction mixture was heated to reflux at 102° C. under a nitrogen atmosphere overnight. The reaction mixture was allowed to cool to below 55° C. whereupon water (250 mL, 2.5 volumes) was added to precipitate out the solid. The light yellow solid was isolated by Buchner filtration and twice washed with 25% aqueous 2-propanol (100 mL) and then once with 2-propanol (100 mL). It was dried in vacuo to provide olanzapine in 86.5% yield (101.7 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1.Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccn(C)n2)n1
Reactant: Cc1cc(Br)ccn1
Product: Cc1cc(-c2cc(C)nc(C(=O)Nc3ccn(C)n3)c2)ccn1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-methylpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white amorphous, MS (ISP): m/e=308.4 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.[C:16](Cl)(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.C([O-])(=O)C>[CH2:16]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCC#Cc1ccc(-c2cccs2)s1
Reactant: O=C(Cl)c1ccccc1
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: C(#Cc1ccc(-c2cccs2)s1)CCOCc1ccccc1
Reaction time: 8 h

Procedure:
0.8 g of 5-(4-hydroxy-1-butynyl)-2,2'-bithiophene was dissolved in 8 ml of pyridine. 1 ml of benzoyl chloride was added at room temperature, stirred for few minutes and kept overnight. The reaction mixture was treated as in acetate example 81. Slightly yellowish crystal was then obtained and the melting point thereof was 61° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].C(N(CC)CC)C>C(#N)C>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:15]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(NC(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.2 %

Procedure:
under an N2 atmosphere, 4-aminobenzoic acid (2.50 g, 18.2 mmol) was dissolved in acetonitrile (100 ml) and treated with 2-chlorobenzoyl chloride (2.43 ml, 19.1 mmol). Triethylamine (2.66 ml, 19.1 mmol) was added and the reaction was allowed to stir at room temperature for four hours. The reaction was concentrated in vacuo, and the resulting solid was partitioned between Et2O and 0.5N NaOH. The layers were separated and the organic layer was discarded. The aqueous layer was acidified to pH 2 with HCl and the aqueous layer was extracted with ethyl acetate. The organic layer was dried Na2SO4, filtered and concentrated in vacuo. The resulting solid was triturated with Et2O, and the solid was collected by filtration to afford 4-(2-chlorobenzamido)benzoic acid (2.72 g, 54.2% yield). ESI m/z=276.1 (M+H+).