Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([I:38])=[C:34]([CH:37]=1)[CH2:35]O>CN(C=O)C>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([I:38])=[C:34]([CH:37]=1)[CH2:35][N:15]=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(Cl)ccc1I
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(Cl)ccc1I
Temperature: 25 °C
Yield: 107.7 %

Procedure:
DPPA (0.442 mL, 2.05 mmol) followed by DBU (0.306 mL, 2.05 mmol) were added to a stirred solution of 5-chloro-2-iodobenzyl alcohol (500 mg, 1.86 mmol) in DMF (10 mL) at 0° C. and the reaction mixture was warmed to room temperature. After 16 h the mixture was warmed to 70° C. for 2 hr. The reaction was then concentrated and the residue was partitioned between EtOAc and 10% NaHCO3. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated to give 5-chloro-2-iodobenzylazide (588 mg): 1H NMR (CDCl3, 400 MHz) δ 4.43 (s, 2H), 7.03 (dd, J=2.6, 8.4 Hz, 1H), 7.39 (d, J=2.6, 1H), 7.78 (d, J=8.4 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>>[C:1]1([CH2:7][C:8]([O:10][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(CBr)cc1
Agent: [Na]
Product: COc1ccc(COC(=O)Cc2ccccc2)cc1

Procedure:
Phenylacetic acid, sodium salt, is reacted with 4-methoxybenzyl bromide to obtain 4-methoxybenzyl phenylacetate;
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH2:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:5].C(N(CC)CC)C.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH:16][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)=[O:32])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:5]
Reactant: O=C(Cl)c1ccccn1
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C12CC3CC(CC(NC(=O)c4ccccn4)(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a round bottom flask was added 3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride (20.0 g, 81.4 mmol) and methylene chloride (500 mL) and the solution was cooled at 0° C. To this solution was then added triethylamine (57 mL, 0.41 mol) followed by picolinoyl chloride hydrochloride (15.2 g, 85.4 mmol; TCI America, Wellesley Hills, Mass., USA) and the reaction was stirred at 0° C. for 30 minutes, then at room temperature for 6 hours. To the reaction was added saturated aqueous sodium bicarbonate (500 mL) and the biphasic mixture was stirred vigorously for a few minutes, then transferred to a 2-L separatory funnel. The mixture was extracted, the layers separated and the aqueous layer was extracted again with methylene chloride (2×200 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 24.8 g (97%) of the title compound, 3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid methyl ester, as a pale brown solid. 1H NMR (400 MHz, CDCl3) δ 8.54-8.49 (m, 1H), 8.16 (dt, J=7.8, 1.0 Hz, 1H), 7.96 (br s, 1H), 7.83 (td, J=7.8, 1.8 Hz, 1H), 7.40 (ddd, J=7.6, 4.8, 1.3 Hz, 1H), 3.66 (s, 3H), 2.34-2.30 (m, 2H), 2.29-2.23 (m, 2H), 2.17-2.13 (m, 4H), 1.97-1.80 (m, 4H), 1.78-1.62 (m, 2H). ESI-MS m/z: 315.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH3:19])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].C(N(C(C)C)C(C)C)C.Cl[C:33]1[N:38]=[C:37]([S:39][C:40]#[N:41])[C:36]([N+:42]([O-:44])=[O:43])=[CH:35][N:34]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([N:18]([CH3:19])[C:33]3[N:38]=[C:37]([S:39][C:40]#[N:41])[C:36]([N+:42]([O-:44])=[O:43])=[CH:35][N:34]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:20]=[CH:21][CH:22]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CNc1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc([N+](=O)[O-])c(SC#N)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the above-mentioned crude product of 3-(1-cyano-1-methylethyl)-N-[3-(methylamino)phenyl]benzamide in tetrahydrofuran (15 mL) were added N-ethyl-N-isopropylpropane-2-amine (345 μL, 1.98 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (314 mg, 1.50 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15→70/30), and the fractions containing the object product were concentrated under reduced pressure to give 2-{[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenyl](methyl)amino}-5-nitropyrimidin-4-yl thiocyanate as a yellow oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [SH2:1].[CH3:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]#[N:12])[CH:6]=[CH:7][C:8]=1[CH3:9].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([NH2:12])=[S:1])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(CC#N)cc1C
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1ccc(CC(N)=S)cc1C

Procedure:
The 3,4-dimethylphenyl(thioacetamide) was prepared by passing a slow stream of hydrogen sulphide through a solution of 3,4-dimethylphenylacetonitrile (56.6 g.) in pyridine (60 ml.) and triethylamine (39.4 g.) during 12 hours. The reaction mixture was evaporated under reduced pressure and the residue was recrystallised from a mixture of benzene and light petroleum (b.p. 60°-80°) to give 3,4-dimethylphenyl (thioacetamide), m.p. 91°-94°.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:22])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:13]([NH:29][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:12][C:11]3=[O:22])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1C=C(O)C(c2ccccc2)N1c1ccc2[nH]cnc2c1
Reactant: NC1CCCCC1
Product: O=C1C=C(NC2CCCCC2)C(c2ccccc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-phenyl-1H-pyrrol-2(5H)-one (0.120 g, 0.366 mmol) and cyclohexylamine (0.59 ml, 5.13 mmol) according to method 7 described above.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ncc2cc(Br)ccc21
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
The crude 5-bromo-1H-indazole (compound 2f; 100 mmol) was dissolved in 250 mL of DMF. K2CO3 (20.7 g, 150 mmol) and 1-bromo-2-methylpropane (16.3 mL, 150 mmol) were added. The mixture was heated to 120° C. under nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Water (200 mL) and CH2Cl2 (200 mL) were added to the residue and stirred vigorously for 30 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4, filtered through Celite, and concentrated under reduced pressure to provide about 30 g of crude material. The crude material was purified by chromatography (1:9 to 1:4 ether/hexanes) to provide 12.870 g of compound 3f as a dark red oil, yielding 50.8% for steps A and B. MS ESI (+) m/z 253 and 255 (M+1) detected. 1H-NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.87 (m, 1H), 7.43 (m, 1H), 7.29 (m, 1H), 7.29 (m, 1H), 4.15 (m, 2H), 2.33 (m, 1H), 0.92 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:3]=1.[CH:17]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+].O>CC(C)=O>[Cl:8][C:6]1[N:7]=[C:2]([NH:24][CH:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:5]=1
Reactant: NC1CCCCCC1
Reactant: Fc1cccc(Nc2nc(Cl)nc(Cl)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Fc1cccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)c1

Procedure:
To 159a (1.0016 g, 3.9 mmol) dissolved in acetone (20 mL) was added a solution of cycloheptylamine (0.5 mL, 3.9 mmol) in acetone (5 mL) followed by addition of 2.5 N NaOH (1.6 mL, 3.9 mmol) and water (4 mL). The reaction mixture was allowed to stir at reflux for 3 hours under nitrogen. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine and dried over potassium carbonate. The filtered sample was concentrated by rotary evaporation and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 70:30 hexanes:ethyl acetate) yielded an off-white solid (159b, 908 mg, 69%), mp 148° C.; HPLC: Inertsil ODS-3V C18, 30:70 [KH2PO4 (0.0M, pH 3.2): CH3CN], 264 nm, Rt 22.3 min, 79.2% purity; MS (TOF MS ES+): m/z 413 (60.4), 338 (44.0), 336 (M+H, 100).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)=[O:4].CI.[C:17]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:14][C:2]([F:1])([F:13])[C:3]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)[CH3:17])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc(I)cc1)C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(C(=O)C(F)(F)F)c1ccc(I)cc1
Temperature: 80 °C

Procedure:
Intermediate 32 (1.0 g, 3.175 mmol) in 20 mL of acetone was combined with CH3I (6.350 mmol, 0.901 g, 0.395 mL) and K2CO3 (6.350 mmol, 0.876 g) then refluxed at 80° C. for 2 hours. The reaction was worked up quenching the reaction with 1× saturated NaHCO3, extracted 4×25 mL EtOAc then washed 1× water, 1× saturated NaCl, dried over Na2SO4, then concentrated. The product was carried through without purification. ES/MS calcd. for C9H7F3INO 328.95. Found m/z=330 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].[Cl:10]N1C(=O)CCC1=O>C(#N)C>[Cl:10][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:9]=[CH:8][C:6]=1[NH2:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1ccc(N)cc1
Solvent: CC#N
Product: N#Cc1ccc(N)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred, 60° C. solution of 4-cyanoaniline (20 g, 0.169 mol) in acetonitrile (200 mL) was added slowly N-chlorosuccinimide (24.8 g, 0.186 mol) to keep the reaction at reflux. After the addition of the N-chlorosuccinimide was complete, the reaction mixture was stirred at 60° C. for two hours. The solvent was then removed under reduced pressure. The residue was then dissolved in dichloromethane, washed with a 5% sodium hydroxide solution, dried (Na2SO4) and evaporated under reduced pressure to afford 24.5 g (95%) of the title compound, 2-chloro-4-cyanoaniline, as a tan solid; m.p. 93°-95° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)=[CH:30][CH:29]=1)(=[O:19])[CH:17]=[CH2:18].[C:43]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][O:54][C:55]1[CH:63]=[CH:62][C:58]([C:59](O)=[O:60])=[CH:57][CH:56]=1)(=[O:46])[CH:44]=[CH2:45]>ClCCl>[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][C:59](=[O:60])[C:58]3[CH:57]=[CH:56][C:55]([O:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][O:47][C:43](=[O:46])[CH:44]=[CH2:45])=[CH:63][CH:62]=3)=[CH:38][CH:37]=2)=[CH:32][CH:33]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)OCCCCCCOc1ccc(CCc2ccc(O)cc2)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(CCc2ccc(OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)cc2)cc1
Yield: 82.4 %

Procedure:
1.01 g of N,N′-dicyclohexyl carbodiimide was added to a mixture of 1.6 g of 4-{2-[4-(6-acryloyloxy-hexyloxy)-phenyl]-ethyl}-phenol (G), 1.43 g of 4-(6-acryloyloxyhexyloxy)benzoic acid, 0.06 g of 4-N,N-dimethylaminopyridine and 10 ml of dichloromethane stirred in an icebath. After stirring for 2 hours, the ice-bath was removed and the mixture was stirred one night at room temperature. 2.3 g of 4-(6-Acryloyloxy-hexyloxy)-benzoic acid 4-{2-[4-(6-acryloyloxy-hexyloxy)-phenyl]-ethyl}-phenyl ester (10, 78%) was obtained after filtration through silica, evaporation and recrystallizing from methanol.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]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(Cl)Cl>[NH2:10][C:8]([C:3]1([NH:2][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[Cl:11])[CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:9]
Reactant: NC(=O)C1(N)CCCC1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)C1(NC(=O)c2ccccc2Cl)CCCC1
Reaction time: 3 h

Procedure:
To a stirred solution of 1-aminocyclopentanecarboxamide hydrochloride (0.46 g, 2.79 mmol) in DCM (4 mL), cooled to 0° C., were added 2-chlorobenzoyl chloride (0.73 g, 4.19 mmol) and triethylamine (0.97 mL, 6.99 mmol). After stirring for 3 h, the precipitate in the reaction mixture was filtered to give the title compound.
Reaction SMILES: [Br-:1].C1(C(O)(C2C=CC=CC=2)C(O[CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH3:27])[CH:17]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[C:18](=[O:20])[NH2:19])=O)CCCCC1.[C:35]([OH:51])(=[O:50])[C:36]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[Br-:1].[OH:37][C:36]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:35]([O:51][C@@H:16]1[CH2:15][CH2:14][N+:13]([CH3:27])([CH:17]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[C:18](=[O:20])[NH2:19])[CH2:12]1)=[O:50]
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Reactant: C[N+]1(C(C(N)=O)c2cnccn2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: [Br-]
Product: C[N+]1(C(C(N)=O)c2cnccn2)CC[C@@H](OC(=O)C(O)(c2ccccc2)c2ccccc2)C1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3-((R/S)-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide (Example 1) by replacing cyclohexyl-hydroxy-phenyl-acetic acid with benzilic acid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.CN(C)CCN(C)C.[Li]CCCC.Cl[C:37]([O:39][CH2:40][Cl:41])=[O:38]>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]2[N:7]([C:37]([O:39][CH2:40][Cl:41])=[O:38])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Reactant: O=C(Cl)OCCl
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc2c(s1)N(C(=O)OCCl)c1ccccc1N=C2N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
To a solution of olanzapine (5.0 g, 16 mmol) in tetrahydrofuran (50 mL) at −78° C. was added tetramethylethylenediamine (2.4 mL, 16 mmol), followed by 2M n-BuLi in hexanes (8.0 mL, 16 mmol) over 5 min. The reaction mixture was stirred for 15 min and then chloromethyl chloroformate (2.1 mL, 24 mmol) added and the reaction mixture stirred a further 30 min. The reaction mixture was then warmed to room temperature, stirred for 1 h and quenched with water (50 mL). This mixture was diluted with brine (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried over MgSO4, evaporated and the residue further purified by column chromatography on silica eluting with 0.2:1:1 methanol/dichloromethane/ethyl acetate to give chloromethyl 2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate [C] (5.6 g, ˜50% pure by 1H NMR and LCMS). This was used directly in the next reaction without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.[CH3:28][C:29]1[S:33][C:32]([C:34]([OH:36])=[O:35])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:27][O:26][C:17]1[CH:18]=[C:19]([O:22][CH2:23][O:24][CH3:25])[CH:20]=[CH:21][C:16]=1[C:4]1[C:3]([CH2:2][O:36][C:34]([C:32]2[S:33][C:29]([CH3:28])=[CH:30][CH:31]=2)=[O:35])=[C:12]2[C:7]([NH:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[NH:11]2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: COCOc1ccc(-c2ccc3c(c2CCl)NC(=O)C(C)(C)N3)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)s2)NC(=O)C(C)(C)N3)c(OC)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A mixture of 8-chloromethyl-7-(2-methoxy-4-methoxymethoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 10, 238 mg, 0.609 mmol), 5-methyl-2-thiophenecarboxylic acid (133 mg, 0.936 mmol), and potassium carbonate (261 mg, 1.89 mmol) was suspended in anhydrous N,N-dimethylformamide (5 mL) and stirred at 80° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL). It was washed with water (100 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (264 mg) as a yellow amorphous product. (Yield 87%)
Reaction SMILES: [O:1]1[CH2:26][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[N:12]=[CH:11][N:10]=1.[CH3:27][NH2:28]>C(O)C.O>[CH3:27][NH:28][CH2:26][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: CN
Reactant: Cc1cccc(Nc2cc(Nc3cccc(OCC4CO4)c3)ncn2)c1
Solvent: CCO
Solvent: O
Product: CNCC(O)COc1cccc(Nc2cc(Nc3cccc(C)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
Using an analogous reaction procedure to that described in Example 33, a mixture of 4-[3'-(2,3-epoxypropoxy)anilino]6-(3'-methylanilino) pyrimidine and 33% methylamine in ethanol and NHP was stirred over 2 days at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The product so obtained was washed with water and with brine, dried (MgSO4) and evaporated. The residue was recrystallised from a mixture of methylene chloride, methanol and hexane to give 4-[3'-(3-methylamino-2-hydroxypropoxy)anilino]6-(3'-methylanilino) pyrimidine is 46% yield, m.p. 88°-90° C.;
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([CH3:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: Cc1ccc(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1

Procedure:
The 1-benzyl-4-aminopiperidine prepared in Example 30 was treated with p-methylbenzoyl chloride in a similar manner to that described in the sameexample and the product converted to a salt.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CC(N(C)C)=O>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:22][CH2:21][CH2:20][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:10])[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1nc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1nc(C(=O)NCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of 6-methyl-5-nitropyridine-2-carboxylic acid (0.500 g, 3.0 mmol) in DCM (7 mL) were added 2-morpholin-4-ylethanamine (1.0 mL, 7.7 mmol), TBTU (0.992 g, 3.1 mmol), and DMA (1.34 mL, 7.7 mmol). The reaction mixture was allowed to stir at rt overnight and then quenched with water. The organic solution was separated and the aqueous solution was extracted with DCM. The organic solutions were combined and concentrated. The residue was purified by column chromatography to give 6-methyl-N-(2-morpholin-4-ylethyl)-5-nitropyridine-2-carboxamide (0.27 g, 30%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][N:26]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH:27]1[CH:33]=O>C1COCC1>[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][N:26]1[CH:27](/[CH:33]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:28][CH2:29][CH2:30][C:31]1=[O:32]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCC#CCN1C(=O)CCCC1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)/C=C/C1CCCC(=O)N1CC#CCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 37 mg, 0.91 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (217 mg, 0.83 mmol) in THF (4 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 50 min at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude from previous reaction, ˜0.92 mmol) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid and water (1:1, 15 mL) and extracted with EtOAc (3×40 mL). The combined organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10% →50% EtOAc/CH2Cl2, gradient) afforded 175 mg (58%) of the title compound.