Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.[CH3:12][S:13][S:14][C:15]([CH3:19])([CH3:18])[CH:16]=O.[BH4-].[Na+]>C(O)C>[CH3:16][C:15]([S:14][S:13][CH3:12])([CH3:19])[CH2:18][NH:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: Nc1cc(CO)cc(CO)c1
Reactant: CSSC(C)(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CSSC(C)(C)CNc1cc(CO)cc(CO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
(5-amino-1,3-phenylene)dimethanol (2.5 g, 16.32 mmol) and 2-(methyldithio)isobutyraldehyde (2.347 ml, 16.32 mmol) were stirred at ambient temperature in absolute ethanol (82 ml) until completely dissolved (3 hours). The mixture was cooled to 0° C. in an ice bath and sodium borohydride (0.741 g, 19.59 mmol) was added. The reaction was stirred for 1 hour at 0° C., and was then quenched slowly with cold 5% HCl solution. The mixture was diluted with dichloromethane and the pH was adjusted to pH=8 with saturated sodium bicarbonate solution then extracted with dichloromethane and then washed with brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (MeOH/DCM) yielded (5-(2-methyl-2-(methyldisulfanyl)propylamino)-1,3-phenylene)dimethanol (3 g, 65%) as a white solid. 1H NMR (400 Hz, CDCl3): δ6.62 (s, 1H), 6.54 (s, 2H), 4.53 (s, 4H), 3.13 (s, 2H), 2.30 (s, 3H), 1.32 (s, 6H). See FIG. 47.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[CH:12]=[C:13]([S:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[O:14]2)=[C:9]([OH:26])[C:8]=1[O:27][CH3:28])[CH2:4][CH3:5])[CH3:2].Cl.Cl.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:47]=[CH:46][C:42]([CH2:43][O:44]Cl)=[CH:41][CH:40]=2)[CH2:34][CH2:33]1.C(N(CC)CC)C>ClCCl>[CH2:1]([CH:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[CH:12]=[C:13]([S:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:43](=[O:44])[C:42]4[CH:41]=[CH:40][C:39]([CH2:38][N:35]5[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]5)=[CH:47][CH:46]=4)=[CH:20][CH:19]=3)[O:14]2)=[C:9]([OH:26])[C:8]=1[O:27][CH3:28])[CH2:4][CH3:5])[CH3:2]
Reactant: CN1CCN(Cc2ccc(COCl)cc2)CC1
Reactant: CCC(CC)Oc1cc2oc(Sc3ccc(O)cc3)cc(=O)c2c(O)c1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)Oc1cc2oc(Sc3ccc(OC(=O)c4ccc(CN5CCN(C)CC5)cc4)cc3)cc(=O)c2c(O)c1OC
Yield: 33.7 %

Procedure:
150 ml in dichloromethane of 4.46 g of 7-(1-ethylpropoxy)-5-hydroxy-2-(4-hydroxyphenylthio)-6-methoxychromone obtained in Example 33, 7.21 g of 4-(4-methylpiperazinomethyl)benzoxychloride dihydrochloride, 7.78 ml of triethylamine was stirred over 3 hours at room temperature. The solution thus reacted was concentrated, and an aqueous solution of sodium bicarbonate was added to the resulting residues, and the product was extracted with ethyl acetate. The organic layer was concentrated, and the residues thus obtained were purified by flash column chromatography (chloroform:methanol=30:1), whereby 2.31 g of 7-(1-ethylpropoxy)-5-hydroxy-2-{4-[4-(4-methylpiperazinomethyl)benzoyloxy]phenylthio}-6-methoxychromone was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1.[CH:33](=O)[CH3:34].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:33][CH3:34])[CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2cccs2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1cccs1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-((2-thienylmethyl)amino)-pentyl)piperidin-4-yl)methyl)benzamide (1.5 g) as starting compound, acetaldehyde (0.23 ml) and sodium cyanoborohydride (0.25 g) were reacted and treated in the same manner as in Example 136 to give 0.96 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(2-thienylmethyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][C:18]([CH3:27])([CH3:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.O.[NH2:29][NH2:30]>C(O)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][C:18]([CH3:27])([CH3:26])[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:30][N:29]=1
Reactant: NN
Reactant: CC(C)(Cc1ccccc1)Nc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: O
Solvent: CCO
Product: CC(C)(Cc1ccccc1)Nc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 120 °C

Procedure:
A mixture of 4-{2-amino-6-[(1,1-dimethyl-2-phenylethyl)amino]-4-pyrimidinyl}-2-fluorobenzonitrile (210 mg, 0.58 mmol) and hydrazine hydrate (99%, 2 mL) in ethanol (3 mL) was stirred and heated at 120° C. for 1 h in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature and concentrated in vacuo. Water (100 mL) was added, and the resulting mixture was filtered. The solids were dried under vacuum to afford the title compound (90 mg) as a yellow solid. LC-MS (ES) m/z=374 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.34 (s, 6H), 3.26 (s, 2H), 5.37 (s, 2H), 6.05 (s, 2H), 6.34 (s, 1H), 6.40 (s, 1H), 7.10-7.25 (m, 5H), 7.39 (d, 1H), 7.70 (d, 1H), 7.84 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[H-].[Na+].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CN(C)C=O.O>[CH3:13][S:14]([N:6]([C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])[S:14]([CH3:13])(=[O:16])=[O:15])(=[O:16])=[O:15]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(c1ccccc1[N+](=O)[O-])S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a cooled (0° C.) solution of 2-nitroaniline (1 g, 7.25 mmol) in dimethylformamide (DMF, 10 mL) was added sodium hydride (608 mg, 25 mmol). After addition was complete methanesulfonyl chloride (1.69 mL, 21.8 mmol) was added and the reaction was warmed to room temperature and stirred for 1 hour. The reaction was then diluted with water and the product extracted with ethyl acetate. The organic layer was concentrated and purified by chromatography to provide N-(methylsulfonyl)-N-(2-nitrophenyl)methanesulfonamide (1.5 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.89 (m, 1H), 7.80 (m, 2H), 3.58 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.I[CH2:26][CH2:27][F:28]>>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:26][CH2:27][F:28])[CH:18]=2)=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Reactant: FCCI
Product: Nc1nc(-c2ccco2)c(-c2ccc(=O)n(CCF)c2)c(-c2ccco2)n1

Procedure:
The title compound was synthesized in a similar manner to Example 66 using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and 1-iodo-2-fluoroethane.
Reaction SMILES: [N:1]1([CH2:6][C@H:7]2[NH:11][CH2:10][C@H:9]([NH:12][C:13]([C:15]3[S:16][C:17]([Cl:20])=[CH:18][CH:19]=3)=[O:14])[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.BrC([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]2=[O:38])=[CH:28][C:27]=1[F:39])C(N)=O>>[F:39][C:27]1[CH:28]=[C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]2=[O:38])[CH:30]=[CH:31][C:26]=1[NH:12][C:13]([CH2:15][N:11]1[C@H:7]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][C@@H:9]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:10]1)=[O:14]
Reactant: O=C(N[C@H]1CN[C@H](CN2CCCC2)C1)c1ccc(Cl)s1
Reactant: NC(=O)C(Br)c1ccc(-n2ccccc2=O)cc1F
Product: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CN1CCCC1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
17.5 Using general procedure A 5-chloro-thiophene-2-carboxylic acid ((3R,5S)-5-pyrrolidin-1-ylmethyl-pyrrolidin-3-yl)-amide was reacted with 2-bromo-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-acetamide (example 11.3) to give 5-chloro-thiophene-2-carboxylic acid ((3R,5S)-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-5-pyrrolidin-1-ylmethyl-pyrrolidin-3-yl)-amide. Light yellow solid. MS 558.2 ([M+H]+)
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](Cl)=[O:29])[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:9]([NH:8][C:28](=[O:29])[CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccc(Cl)c1
Temperature: 0 °C

Procedure:
Triethylamine (18 mL, 130 mmol) was added to methyl 2-amino-5-bromobenzoate (25 g, 110 mmol) in DCM (150 mL). The mixture was cooled to 0° C. and 2-(3-chlorophenyl)acetyl chloride (24.3 g, 130 mmol) in DCM (100 mL) was added. The mixture was allowed to warm to room temperature overnight with stirring. Aqueous K2CO3 (10 wt. %) was added and the mixture was extracted with DCM. The organic phase was dried (MgSO4), filtered, and concentrated to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[C:12]1(=[O:17])[O:16][CH:14]([CH3:15])[CH2:13]1.Cl>[OH-].[Na+]>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH:14]([CH3:15])[CH2:13][C:12]([OH:17])=[O:16]
Reactant: CC1CC(=O)O1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(CC(=O)O)Oc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 15.1 %

Procedure:
A solution of 40.5 g (0.25 mol) m-trifluoromethylphenol in 100 ml 2.5N sodium hydroxide was heated at reflux and 20.4 ml (0.25 mol) beta-butyrolactone was added dropwise over 50 minutes. The reaction was cooled to 0° C. and 3 ml concentrated hydrochloric acid was added to bring the pH to 7. The reaction was extracted with 3×100 ml diethyl ether. The pH of the aqueous was brought to 2 with 20 ml concentrated hydrochloric acid and then the aqueous was extracted with 2×100 ml diethyl ether. The latter combined ether extracts were washed with 100 ml water and 100 ml brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 9.4 g (15%) of 3-[3-(trifluoromethyl)phenoxy]-butyric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:21]([C:24]1[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CC(O)=O.CO>[CH3:20][N:16]1[N:15]=[C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:4]=[CH:3][C:2](/[N:1]=[CH:29]/[C:27]4[O:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=4)=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)[O:18][C:17]1=[O:19]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Cn1nc(C2CCN(c3ccc(N)cc3)CC2)oc1=O
Solvent: CO
Solvent: CC(=O)O
Product: Cn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Yield: 86 %

Procedure:
5-[1-(4-Aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7b, 0.27 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 3-methyl-5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9b, 341 mg, 86%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C@H:5]([N:10](OC(C)(C)C)C(C(OC(C)(C)C)=O)=O)[C:6]([O:8]C)=[O:7].[ClH:25]>>[ClH:25].[NH2:10][C@@H:5]([CH2:4][CH2:3][CH2:2][Br:1])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)[C@H](CCCBr)N(OC(C)(C)C)C(=O)C(=O)OC(C)(C)C
Agent: Cl
Product: N[C@@H](CCCBr)C(=O)O
Yield: 98 %

Procedure:
Finally, 2.33 g of methyl(S)-5-bromo-2-{(tert-butoxy)-N-[(tert-butyl)oxy-carbonyl]carbonylamino}-1-pentanoate was stirred in 50 ml of 4N HCl at 60° C. for 24 hours and then concentrated to obtain 1.29 g (98%) of (S)-2-amino-5-bromo-pentanoic acid hydrochloride.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH:11]=[CH:12][CH:13]=[CH:14][C:15]([OH:17])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:24][OH:25]>ClCCl.O1CCCC1>[OH:25][NH:24][C:15](=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH2:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=C(O)C=CC=CCS(=O)(=O)c1ccccc1
Reactant: NO
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(C=CC=CCS(=O)(=O)c1ccccc1)NO
Reaction time: 1 h
Yield: 29.6 %

Procedure:
To a solution of 6-benzenesulfonyl-hexa-2,4-dienoic acid (0.292 g, 1.15 mmol) in dry dichloromethane (5 mL) was added dropwise oxalyl chloride, at 0° C. under an atmosphere of argon. One drop on dimethylformamide was then added. After stirring at 2020 C. for one hour, a solution of aqueous hydroxylamine (50%, 0.17 mL, 2.5 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred for an additional hour and concentrated under reduced pressure to give a yellow foam that was purified by column chromatography (8:2 ethyl acetate:40-60° C. petroleum to 100% ethyl acetate). The title compound (91 mg, 31%) was obtained as a white foam.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.O>CN(C)C=O>[N:13]1([C:4]2[N:3]=[C:2]([O:1][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1O
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 79.2 %

Procedure:
To a solution of ethyl 4-hydroxy-2-(2,3-dihydro-1H-indol-1-yl)-5-pyrimidinecarboxylate (7.1 g, 27.6 mmol) in N,N-dimethylformamide (100 ml) were added potassium carbonate (7.8 g, 60 mmol) and 4-fluorobenzylbromide (3.74 ml, 30 mmol) and the mixture was stirred at 80° C. for 18 h. The reaction mixture was allowed to cool to room temperature and water was added. The precipitated crystals were collected by filtration, washed several times with cold water and cold ether and dried to give the title compound (8.6 g, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)[C:5]([O:7][CH3:8])=[O:6].CCN(C(C)C)C(C)C.[CH2:33]([O:36][CH2:37][CH2:38]Br)[CH2:34]Br>C1(C)C=CC=CC=1>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[N:1]1[CH2:38][CH2:37][O:36][CH2:33][CH2:34]1)[CH:21]=[CH:20]2
Reactant: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2)c(N)c1
Reactant: BrCCOCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2)c(N2CCOCC2)c1
Temperature: 110 °C
Yield: 80.3 %

Procedure:
To a solution of methyl 3-amino-4-(6-methoxynaphthalen-2-yl)benzoate (1.00 g, 3.30 mmol) (see Step 1 of Example 5) and DIPEA (1.70 g, 13.2 mmol) in anhydrous toluene (20 mL) containing catalytic amount of KI (100 mg, 0.660 mmol) was added 2,2′-dibromodiethyl ether (1.50 g, 6.60 mmol). The mixture was heated to 110° C. for 3 days. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (PE/EtOAc=10/1) to give the product (1.00 g, yield 81%).
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.C(O)CC>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: CN1CCNCC1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Solvent: O
Solvent: CCCO
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 110 °C
Yield: 89 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (5 g, 0.02 mol), N-methylpiperazine (12.5 mL, 2.5 vol) and 1-propanol (15 mL, 3 vol) were charged into a three-necked round bottom flask equipped with a reflux condenser, overhead stirrer, and thermometer. The reaction mixture was heated slowly to 110° C. under a nitrogen atmosphere and then refluxed overnight. The reaction mixture was cooled to below 50° C. whereupon water (15 mL, 3 volumes) was added to precipitate out the solid, which was isolated by Buchner filtration. The resulting light yellow solid was washed twice with water (5 mL) and dried to afford olanzapine in 89% yield (5.22 g).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].[CH2:9]([O:11][C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)[CH3:10].C(I)C>O1CCCC1>[CH2:1]([CH:13]([CH2:14][CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)[C:12]([O:11][CH2:9][CH3:10])=[O:22])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)CCCC1(C)OCCO1
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)CCC1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
To a freshly prepared solution of lithium diisopropylamide (40.0 mmol in tetrahydrofuran/hexane; 50 mL, 1:1) at −78° C. was added a solution of ethyl-4-(2-methyl-1,3-dioxolan-2-yl)butanoate (6.7 g, 33.3 mmol) in tetrahydrofuran (15 mL) over 15 minutes. After stirring for 15 minutes, ethyl iodide (4.0 mL, 50.0 mmol) was added rapidly via syringe. The reaction was stirred at −78° C. for 6 hours and then allowed to warm slowly to ambient temperature and stir for 16 hours. The reaction was quenched by the addition of water (50 mL) and extracted with ether (3×50 mL). The combined organics were washed with brine (50 mL), dried (magnesium sulfate), concentrated in vacuo and chromatographed (silica gel, ethyl acetate/hexane, 1:4) to afford ethyl 2-ethyl-4-(2-methyl-1,3-dioxolan-2-yl)butanoate (2.6 g, 33%) as a colorless liquid.
Reaction SMILES: C([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([NH2:15])=[O:14])=[C:9]([OH:16])[CH:8]=[CH:7][CH:6]=2)C.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.O>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:16][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:11]([CH2:12][C:13]([NH2:15])=[O:14])=[CH:3][N:4]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CBr
Reactant: CCc1c(CC(N)=O)c2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c(CC(N)=O)cn2Cc1ccccc1
Reaction time: 1.5 h
Yield: 21.9 %

Procedure:
2-Ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide (135 mg, 0.44 mmol) was added to 17.6 mg (0.44 mmol) of NaH/mineral oil (washed with hexanes) in 5 mL of DMF, stirred 1.5 hours, 0.04 mL (0.44 mmol) of methyl 2-bromoacetate added and stirring maintained for 3 hours. The mixture was diluted with water, extracted with ethyl acetate. The ethyl acetate was washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel eluting with 2% MeOH/ethyl acetate to give 34 mg (34% yield) of 2-[[3-(2-amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]#[N:18].CS(C)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCOc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A mixture of 64.25 g of 4-chlorophenol, 98 g of anhydrous potassium carbonate, 40 g of chloroacetonitrile and 100 ml of dimethyl sulfoxide was heated with stirring in a 500 ml round-bottomed three-necked flask at 70°-80° C. for 3.0 hours. The reaction mixture was then poured into ice and water. After the ice melted, the mixture was filtered and the product washed well with water which gave 77.5 g of 4-chlorophenoxyacetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]([SH:12])=[N:9]2)=[CH:4][CH:3]=1.Cl[Sn:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]([S:12][Sn:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Cl)cc2nc(S)n1-c1ccccc1
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c2ccc(Cl)cc2nc(S[Sn](c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 4 g (0.014 mole) 7-chloro-2-mercapto-3-phenyl-4(3H)-quinazolinone (the product of Example 3) and 5.4 g (0.014 mole) chlorotriphenyl tin in methylene chloride (about 75 ml), 1.4 g (0.014 mole) triethylamine in methylene chloride (about 25 ml) was added dropwise. The resulting mixture was stirred for about one hour at ambient temperature, refluxed about 5 hours, stirred overnight, refluxed about 4 hours and cooled. The mixture was washed with water. The organic fraction was dried and stripped to give the above-identified product as a solid, melting point 110° to 112° C.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[N:16][C:17]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25](C3CCCCO3)[N:24]=[CH:23]4)=[CH:18][C:4]=2[N:3]1[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38].Cl.ClCCl>O1CCOCC1>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([NH:19][C:17]3[N:16]=[CH:15][C:5]4[N:6]([C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=5)[C:7](=[O:8])[CH:2]([CH3:1])[N:3]([CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])[C:4]=4[CH:18]=3)=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: CC(C)CCN1c2cc(Nc3ccc4c(cnn4C4CCCCO4)c3)ncc2N(c2ccccc2)C(=O)C1C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)CCN1c2cc(Nc3ccc4[nH]ncc4c3)ncc2N(c2ccccc2)C(=O)C1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a stirred solution of 2-methyl-1-(3-methylbutyl)-4-phenyl-7-{[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]amino}-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one (15 mg) in dioxane (2 mL) was added 2N aq. HCl (2 mL) at rt. The resulting mixture was stirred at rt for 2 h. LC-MS indicated completion of reaction. Dichloromethane (30 mL) was added to the reaction mixture, the organic phase was washed with aq. NaHCO3, dried over anhydrous sodium sulfate, and evaporated to give a residue, which was purified by preparative Thin-Layer Chromatography (developing solvent: 2% methanol in dichloromethane) to give the desired product (yield: 60%) 1H NMR (400 MHz, CD3OD) b 0.88 (d, J=6.4 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H), 1.41 (d, J=6.82 Hz, 3H), 1.55-1.65 (m, 3H), 3.18-3.28 (m, 1H), 3.39-3.49 (m, 1H), 4.26 (q, J=6.74 Hz, 1H), 6.10 (s, 1H), 6.79 (s, 1H), 7.27-7.34 (m, 3H), 7.49-7.55 (m, 2H), 7.56-7.62 (m, 2H), 7.75 (d, J=1.52 Hz, 1H), 7.97 (s, 1H). MS(ES+): m/z 441.19 [MH+]. HPLC: tR=2.55 (ZQ3, Polar_5 min).