Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg+2].[Cl-].[Cl-].[Br:15][C:16]1[CH:17]=[C:18]([C:24]2([C:30](O)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].S(Cl)(Cl)=O>C(#N)C>[Br:15][C:16]1[CH:17]=[C:18]([C:24]2([C:30]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(C2(C(=O)O)CCOCC2)cc1Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(OC)c(Br)c2)CCOCC1
Temperature: 0 °C
Yield: 16.1 %

Procedure:
A mixture of diethyl malonate (2.8 g, 17 mmol) in 50 mL ACN was stirred at 0° C. This mixture was treated with MgCl2 (1.7 g, 17 mmol) in one portion and dropwise with TEA (3.9 g, 38 mmol). The resulting mixture was then stirred at room temperature for 2.5 hours. A mixture of 4-(3-bromo-4-methoxyphenyl)-tetrahydro-2H-pyran-4-carboxylic acid (5.5 g, 17 mmol) in thionyl chloride (21 g, 175 mmol) was refluxed for 2 hours and then concentrated in vacuo. The residue was diluted with 10 mL ACN and added dropwise to the above mixture. The mixture was stirred at 50° C. for 15 hours, M−1=455/457. The mixture was cooled to room temperature, diluted with 100 mL ether, washed with H2O (2×50 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-20% EtOAc/hexane to give 1.25 g of the intermediate as a pale yellow oil. MS m/e=455/457 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][NH:35][CH3:36])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:35]([CH3:36])[CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:23]([O:22][CH3:21])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26])#[N:7]
Reactant: CNCCc1ccc(OC)c(C(=O)OC)c1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: COC(=O)c1cc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)ccc1OC

Procedure:
Reaction of 1f with 2h produced 3ag. MS found M+H=483. The oxalate salt of 3ag was recrystallized from ethyl acetate; mp 76-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[S:6])[NH2:5].[CH3:12]C(C)=O.[I:16]C>C(#N)C.O>[IH:16].[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([S:6][CH3:12])=[NH:5]
Reactant: CC(C)=O
Reactant: NC(=S)c1c(F)cccc1Cl
Reactant: CI
Solvent: CC#N
Solvent: O
Product: CSC(=N)c1c(F)cccc1Cl
Product: I
Yield: 46.9 %

Procedure:
Into a 50 mL three necked round bottom flask equipped with a magnetic stirrer was added 2-chloro-6-fluorobenzthioamide (3.78 g, 20 mmol) and acetone (20 mL). Dropwise was added iodomethane (2.84 g, 1.24 mL, 20 mmol) and the mixture was allowed to stir at room temperature overnight with monitoring via HPCL (60/40 acetonitrile/water). The solids were removed via filtration and washed with small portions of acetone to give methyl 2-chloro-6-fluorobenzthioimidate hydroiodide as a light yellow solid: 3.1 g (46.9% yield): 1H NMR (DMSO-d6) δ7.7 (m, 1H), 7.5 (m, 2H), 2.7 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]#[N:16])[N:5]([NH:7]C(=O)OC(C)(C)C)[CH:6]=1.O1CCOCC1.[ClH:23].O1CCOCC1.CCCCCC>C(OCC)C>[ClH:23].[NH2:7][N:5]1[CH:6]=[C:2]([Br:1])[CH:3]=[C:4]1[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)Nn1cc(Br)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCOCC
Product: N#Cc1cc(Br)cn1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1 L, 3-neck flask was fitted with a mechanical stirrer, nitrogen inlet, thermocouple and thermocontroller, cooling bath and an addition funnel. tert-Butyl (4-bromo-2-cyano-1H-pyrrol-1-yl)carbamate (19 g, 66 mmol) was added and dissolved with 1,4-dioxane (50 mL), then the stirred orange solution was cooled to 0° C. and HCl/dioxane (4N, 100 mL, 8 eq.) was slowly added from the addition funnel, maintaining an internal temperature around 25° C. After 2 hours, the solution became cloudy and stirring at room temperature was continued for 7 hours. The reaction was monitored for completion by TLC (silica gel, 1:3 EtoAc/hexane, UV; Note: the free base may be observed as a high-Rf spot and can be misinterpreted as incomplete reaction). The reaction mixture was diluted with diethyl ether (150 mL) and the precipitated solids were collected by suction filtration and washed with ether (200 mL). Drying (vacuum oven at 50° C.) afforded the desired product as 10.9 g (93%) of a white solid. 1H-NMR (DMSO): δ 7.24 (d, 1H, J=2 Hz), 6.93 (d, 1H, J=2 Hz), 6.2 (bs, 3H, J=2.8, 4.4 Hz); MS: GC/MS, m/z=[M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Nc1cccc(Cl)c1
Product: Clc1cccc(Nc2ccc(Br)cn2)c1
Temperature: 180 °C

Procedure:
A 1-dram vial was charged with 2,5-dibromopyridine (0.5 g, 2.1 mmol, 1.0 equiv) and 3-chlorophenyl amine (0.89 mL, 8.4 mmol, 4 equiv). The neat reaction mixture was heated to 180° C. for 3 hours. The reaction was cooled, then purified by flash chromatography to afford the title compound. (M+H)+285.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.O.NN.NC(C1C=CC=CC=1Cl)C1C=CC([Cl:36])=CC=1N1C(C)=NN=C1C1CC1>C(O)COCCO>[NH2:8][CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])[C:6]1[CH:24]=[CH:2][C:3]([Cl:36])=[CH:4][C:5]=1[N:11]1[C:10]([CH3:9])=[N:14][N:13]=[C:12]1[CH2:15][OH:16]
Reactant: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: Cc1nnc(C2CC2)n1-c1cc(Cl)ccc1C(N)c1ccccc1Cl
Agent: NN
Solvent: O
Solvent: OCCOCCO
Product: Cc1nnc(CO)n1-c1cc(Cl)ccc1C(N)c1ccccc1Cl

Procedure:
A mixture of 10.776 g. 8-chloro-6-(o-chlorophenyl)-1-hydroxymethyl-4H-s-triazolo[4,3-a] [1,4]benzodiazepine (111) (30.0 mmoles) and 7.50 ml. of hydrazine hydrate in 60 ml. of diethylene glycol is heated to 150°-160° C. for about 18 hours. The reaction is then quenched in a cold aqueous 5% sodium hydroxide solution and the product extracted with chloroform. The extracts thus obtained are dried over anhydrous magnesium sulfate and concentrated in vacuo to give 13.0 g. of oil which is crystallized from methanol/ethyl acetate to give 1.93 g. of a mixture of the A and B isomers (ratio 81/19) of 4-[α-amino-4-chloro-α-(o-chlorophenyl)-o-tolyl]-3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazole (I) m.p. 205°-215° C. The mixture thus obtained is recrystallized from the same solvent mixture to give 0.76 g. of 4-[α-amino-4-chloro-α-(o-chlorophenyl)-o-tolyl]-o-tolyl]-3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazole (I), (isomer A) melting at 218° - 223° C., and having infrared (mull) spectral absorptions at 3330, 3240, 3150, 3060, 2680, 1600, 1570, 1530, 1515 and 1485 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH2:8]O.P(Br)(Br)[Br:12].O>C(Cl)(Cl)Cl>[Br:12][CH2:8][C:7]1[C:2]([F:1])=[CH:3][N:4]=[CH:5][C:6]=1[F:10]
Reactant: OCc1c(F)cncc1F
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1cncc(F)c1CBr
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
To a solution of (3,5-difluoropyridin-4-yl)methanol (3.5 mmol) in anhydrous chloroform (15 mL) was added dropwise a solution of phosphorus tribromide (330 μL, 3.5 mmol) in anhydrous chloroform (5 mL) at 0° C. The mixture was stirred for 6 hours at room temperature. Water was added, and the reaction was extracted 3 times with dichloromethane. The combined organic phases were washed with brine and dried over magnesium sulfate. After evaporation of the solvent, 4-(bromomethyl)-3,5-difluoropyridine was obtained as pale yellow solid (600 mg, 83% yield for 2 steps) and used in the next step without purification; 1H NMR (400 MHz, MeOd4): δ 4.59 (s, 2H), 8.42 (s, 2H).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[C:5]([Si:9]([O:22][CH2:23][C:24]1[CH:29]=[C:28](Br)[CH:27]=[C:26](Br)[CH:25]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:8])([CH3:7])[CH3:6]>C(N(CC)CC)C.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>[OH:4][CH2:1][C:2]#[C:3][C:26]1[CH:25]=[C:24]([CH2:23][O:22][Si:9]([C:5]([CH3:7])([CH3:6])[CH3:8])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:29]=[C:28]([C:3]#[C:2][CH2:1][OH:4])[CH:27]=1
Reactant: CC(C)(C)[Si](OCc1cc(Br)cc(Br)c1)(c1ccccc1)c1ccccc1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCc1cc(C#CCO)cc(C#CCO)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
Pd(Ph3P)4 (520 mg), CuBrSMe2 (200 mg) and propargyl alcohol (3.08 ml, 35.1 mmol) are added successively to a solution of tert-butyl-(3,5-dibrombenzyloxy)diphenylsilane (A1, 5.0 g, 9.9 mmol) in triethylamine (50 ml), and the mixture is stirred at RT for 10 min and then under reflux at 80° C. for 2.5 h. After cooling, the reaction mixture is filtered off with suction through kieselguhr, and the filter cake is washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (8:2)] on a silica gel column. This gives the title compound (4.0 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.48.
Reaction SMILES: [F:1]C1C=CC(C(=O)CN(CC2C=CC=CC=2)CC2C=CC=CC=2)=CC=1S(N)(=O)=O.C1(CCC(=O)C)C=CC=CC=1.[ClH:41].[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH:49]([OH:62])[CH2:50][NH:51][CH:52]([CH3:61])[CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:45][C:44]=1[S:63]([NH2:66])(=[O:65])=[O:64]>>[ClH:41].[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH:49]([OH:62])[CH2:50][NH:51][CH:52]([CH3:61])[CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][C:58]([F:1])=[CH:57][CH:56]=2)=[CH:45][C:44]=1[S:63]([NH2:66])(=[O:65])=[O:64]
Reactant: CC(CCc1ccccc1)NCC(O)c1ccc(F)c(S(N)(=O)=O)c1
Reactant: NS(=O)(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1F
Agent: CC(=O)CCc1ccccc1
Agent: Cl
Product: CC(CCc1ccc(F)cc1)NCC(O)c1ccc(F)c(S(N)(=O)=O)c1

Procedure:
In a similar manner 2-fluoro-5-[[bis(phenylmethyl)amino] acetyl]-benzenesulphonamide (2.5 g) and 4-phenyl-butan-2-one (5 g) were converted into 2-fluoro-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulphonamide, hydrochloride, 0.4 g, m.p. BO°-95°.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[CH3:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[CH3:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)O)c2F)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]phenoxy]acetate (120 mg, 0.27 mmol, 1.0 eq.) in a mixture of THF (5 mL) and MeOH (5 mL) at room temperature was added NaOH (2M aqueous solution, 5 mL, 10 mmol). The reaction was stirred at room temperature for 3 h. The reaction was then diluted with EtOAc and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) filtered and evaporated in vacuo to give the title compound as a gummy solid (112 mg, 94%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:14]2[C:9]3([CH:18]=[CH:17][CH:16]=[CH:15][C:10]3=[N:11][CH2:12][CH2:13]2)[S:8][CH2:7]1)=[O:5])[CH3:2].[CH2:19]=O>>[CH2:1]([O:3][C:4]([CH:6]1[CH:14]2[C:9]3([CH:18]=[CH:17][CH:16]=[CH:15][C:10]3=[N:11][CH2:12][CH2:13]2)[SH:8]([CH3:19])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CSC23C=CC=CC2=NCCC13
Reactant: C=O
Product: CCOC(=O)C1C[SH](C)C23C=CC=CC2=NCCC13

Procedure:
1-Methyl-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester was synthesized by following the same procedure as the synthesis of 1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester in Example 1 except that 19.5 g of acetadehyde was used in place of 10.2 ml of formalin in Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:3]=1.[O:32]1CCC[CH2:33]1.C[O-].[Na+]>CO>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)[N:3]=[C:2]([O:32][CH3:33])[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(Cl)n2)cc1Cl
Reactant: C1CCOC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Combine a mixture of 2-chloro-4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (47 mg, 1 mmol), tetrahydrofuran (1 mL), and a 21% solution of sodium methoxide in MeOH (0.5 mL). Let the reaction stir at 60° C. for 16 hours. Evaporate the mixture, add water (5 mL), and extract twice with EtOAc (5 mL each). Combine the organic layers, dry (Na2SO4), and purify by preparative TLC (8:1 hexanes/EtOAc) to obtain 4-(3-chloro-4-fluoro-phenyl)-2-methoxy-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine.
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:24]=1[C:25]([F:28])([F:27])[F:26])=O)(=O)OC.O.[NH2:37][NH2:38]>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([N:23]2[C:24]([C:25]([F:28])([F:27])[F:26])=[C:20]([C:18]3[N:38]=[N:37][C:2]4[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]=4[CH:17]=3)[CH:21]=[N:22]2)=[CH:30][CH:31]=1
Reactant: COP(=O)(CC(=O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F)OC
Reactant: NN
Reactant: O=C1CCCCCCC1=O
Solvent: O
Product: Fc1ccc(-n2ncc(-c3cc4c(nn3)CCCCCC4)c2C(F)(F)F)cc1

Procedure:
off-white solid. MS (EI): 390.1 (M+). Prepared from cyclooctane-1,2-dione, {2-[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-2-oxo-ethyl}-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([NH:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(-c2ccc(N)nc2C)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(NC(C)=O)nc2C)cc1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
A stirred solution of methyl 4-(6-amino-2-methylpyridin-3-yl)benzoate (Description 7 in EP 97/17351, 300 mg, 1.2 mmole) and pyridine (0.16 ml, 2.0 mmole) in DCM (35 ml) at 0° C. under argon was treated with acetyl chloride (120 mg, 1.5 mmole) and allowed to warm to room temperature over 1 h. Additional acetyl chloride (120 mg) was added, the mixture maintained at room temperature for a further 1 h, then washed with 10% Na2CO3 solution, dried (Na2SO4) and concentrated under vacuum to afford the title compound as a white solid (344 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[S:6][C:7]([CH3:12])=[CH:8][C:9]=1[C:10]#[N:11].ClCCl.O.[CH3:21][N:22]1[CH2:27][CH2:26]N[CH2:24][CH2:23]1>Cl.CN1CCNCC1>[CH3:12][C:7]1[S:6][C:5]2[NH:4][C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[N:1]=[C:10]([N:11]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[C:9]=2[CH:8]=1
Reactant: Cc1cc(C#N)c(Nc2ccccc2N)s1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 120 °C

Procedure:
2-(2-Aminoanilino)-5-methylthiophene-3-carbonitrile (10.0 g) is taken in N-methyl-piperazine (60 ml) and N-methyl-piperazine hydrochloride (24 gm). The solution is heated at 120° C. until completion of reaction. The reaction mass is cooled and dichloromethane (100 ml) and water is added. The mixture is cooled up to room temperature and dichloromethane layer is separated. 50 ml dichloromethane is evaporated and cyclohexane is added in clear solution. On Cooling the solution, solid is separated out, which is filtered and dried under vacuum to get Olanzapine Form I. (Purity >99.6%)
Reaction SMILES: Cl.[F:2][C:3]([F:35])([F:34])[C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:7][N:8]([CH3:26])[C:9]([N:11]1[C@@H:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[CH3:25])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].C=O.[C:38](OC(OC(=O)C)(OC(=O)C)C(O[BH3-])=O)(=O)C.[Na+]>ClCCCl>[F:35][C:3]([F:34])([F:2])[C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:29]=1)[CH2:7][N:8]([CH3:26])[C:9]([N:11]1[C@@H:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[CH3:25])[CH2:16][CH2:15][N:14]([CH3:38])[CH2:13][CH2:12]1)=[O:10]
Reactant: [BH3-]OC(=O)C(OC(C)=O)(OC(C)=O)OC(C)=O
Reactant: Cc1cc(F)ccc1[C@H]1CCNCCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc(F)ccc1[C@H]1CCN(C)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 23.6 %

Procedure:
A mixture of example 2 (53 mg), aqueous formaldehyde (33 μL) and sodium triacetoxyacetoxyborohydride (50 mg) in anhydrous 1,2-dichloroethane (2 mL) was stirred at r.t. overnight. The mixture was washed with water (2 mL) and brine (2 mL) and concentrated in vacuo. The residue was purified by flash chromatography (AcOEt 100%) to give 7-(R)-(4-fluoro-2-methyl-phenyl)-4-methyl-[1,4]-diazepane-1-carboxylic acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide (12 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.IC.[C:17](=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH3:17])[N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC(c2ccc(Cl)nc2)=NN1
Agent: [Cs+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CI
Product: Cn1nc(-c2ccc(Cl)nc2)ccc1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To 6-(6-chloropyridin-3-yl)-4,5-dihydro-2H-pyridazin-3-one (1.03 g, 4.93 mmol) in DMSO (40 mL) was added iodomethane (460 μL, 7.4 mmol) and cesium carbonate (3.2 g, 9.86 mmol). After overnight stirring at 100° C. open to air, the reaction was cooled, diluted with dichloromethane, washed several times with water/brine, dried over sodium sulfate, and concentrated under vacuum to obtain 835 mg product (79%); MS m/z 222 (M+H).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[NH2:23][C:24]1[CH:25]=[C:26]([C:30]2([CH3:37])[NH:35][C:34](=O)[CH2:33][O:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>COCCOC>[NH2:23][C:24]1[CH:25]=[C:26]([C:30]2([CH3:37])[NH:35][C:34](=[S:10])[CH2:33][O:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: CC1(c2cccc(N)c2)COCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: CC1(c2cccc(N)c2)COCC(=S)N1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Lawesson's reagent (0.69 g, 1.64 mmol, 1.3 eq.) was added in one portion to a suspension of 5-(3-amino-phenyl)-5-methyl-morpholin-3-one (0.26 g, 1.26 mmol) in 1,2-dimethoxyethane (10 ml); the reaction mixture was stirred at 80° C. for 18 hours. After complete conversion, the solvent was partially removed at reduced pressure and the dark orange oil diluted with dichloromethane (5 ml) before washing with 1 M HCl (2×5 ml). The aqueous phase was brought to pH 8 and extracted with dichloromethane (4×10 ml) to yield the (RS)-5-(3-amino-phenyl)-5-methyl-morpholine-3-thione as a yellow oil (0.16 g, 57% of theory). Mass (calculated) C11H14N2OS [222.31]; (found) [M+H]+=223.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([CH:12]([OH:15])[CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:9]=1[CH3:10])[CH:7]=[O:8].Cl[C:18]1[C:19](O)=[C:20]([CH:28](O)[CH2:29][CH2:30][CH2:31]C)C(O)=[C:22]([C:25]=1C)C=O.ClC1C(O)=C(C(O)CCCCCC)C(O)=C(C=1C)C=O.ClC1C(O)=C(C(O)CCCCCCCC)C(O)=C(C=1C)C=O.ClC1C(O)=C(C(O)CCCCCCCCC)C(O)=C(C=1C)C=O>>[Cl:1][C:2]1[C:3]([OH:16])=[C:4]([CH:12]([OH:15])[CH2:13][CH2:14][CH2:22][CH2:25][CH2:18][CH2:19][CH2:20][CH2:28][CH2:29][CH2:30][CH3:31])[C:5]([OH:11])=[C:6]([C:9]=1[CH3:10])[CH:7]=[O:8]
Reactant: CCCCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Reactant: CCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Agent: CCCCCCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Agent: CCCCCCCCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Agent: CCCCCCCCCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Product: CCCCCCCCCCCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O

Procedure:
In addition to this compound, 5-chloro-2,4-dihydroxy-3-(1-hydroxypropyl)-6-methylbenzaldehyde (196-3), 5-chloro-2,4-dihydroxy-3-(1-hydroxypentyl)-6-methylbenzaldehyde (196-5), 5-chloro-2,4-dihydroxy-3-(1-hydroxyheptyl)-6-methylbenzaldehyde (196-7), 5-chloro-2,4-dihydroxy-3-(1-hydroxynonyl)-6-methylbenzaldehyde (196-9) and 5-chloro-2,4-dihydroxy-3-(1-hydroxydecyl)-6-methylbenzaldehyde (196-10) were synthesized by the same reaction with the use of respective corresponding starting raw materials.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([N:6]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:7][C:8](=[O:33])[C@@H:9]([CH:14]([C:23](=[O:32])[NH:24][O:25]C1CCCCO1)[CH2:15]/[CH:16]=[CH:17]/[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:5])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:1][C@@H:2]([C:4]([N:6]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:7][C:8](=[O:33])[C@@H:9]([CH:14]([C:23](=[O:32])[NH:24][OH:25])[CH2:15]/[CH:16]=[CH:17]/[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:5])[CH3:3]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)N)C(C/C=C/c1cccs1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)N)C(C/C=C/c1cccs1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
A solution of 0.180 g of (E)-2′-(D-alanyl)-2(R)-[1(RS)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-(2-thienyl)-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of methanol was treated with 0.077 g of p-toluenesulphonic acid monohydrate. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was purified by column chromatography on silica gel, using dichloromethane/methanol (95:5) for the elution, to give 0.056 g of (E)-2′-(D-alanyl)-2(R)-[1(RS)-(hydroxycarbamoyl)-4-(2-thienyl)-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of an off-white solid.