Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:17]#[N:18])[CH2:10][CH2:11][C:12](OCC)=[O:13])=[CH:4][CH:3]=1>[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:17][NH:18][C:12](=[O:13])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(C#N)Cc1ccc(Cl)cc1
Agent: [Ni]
Product: O=C1CCC(Cc2ccc(Cl)cc2)CN1

Procedure:
In the same manner as Example 1-(d), 5 g of ethyl 5-(4-chlorophenyl)-4-cyanovalerate was reduced with Raney's nickel as the catalyst to obtain 5-(4-chlorobenzyl)-2-piperidinone.
Reaction SMILES: [Br:1]Br.[CH2:3]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])[C:14]=3[C:4]1=2.C([O-])(=O)C.[Na+]>CO>[Br:1][C:8]1[C:5]2[O:6][CH2:7][CH2:3][C:4]=2[C:14]2[C@H:13]([CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH2:12][CH2:11][C:10]=2[CH:9]=1
Reactant: CCC(=O)NCC[C@@H]1CCc2ccc3c(c21)CCO3
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)NCC[C@@H]1CCc2cc(Br)c3c(c21)CCO3
Reaction time: 1.5 h
Yield: 93 %

Procedure:
Bromine was added dropwise into a solution of (S)—N-(2-[1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl)propionamide (27.4 g, 0.11 mol) and sodium acetate (10.4 g, 0.13 mol) in methanol (200 mL) with ice-cooling. The mixture was allowed to stir for 1.5 hours with ice-cooling, which was quenched with sodium hydrogen sulfite and poured into water, followed by extracting with ethyl acetate. The extracted solution was washed with water and a saturated aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate:hexane=8:2) to afford the title compound (yield 33.1 g, 93%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].N1(C2C=CN=CC=2)CCCC1.[C:23](O)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CC(C)(C)O
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.7 %

Procedure:
A mixture of 2-bromophenylacetic acid (5.02 g), N,N-dicyclohexylcarbodiimide (5.3 g), 4-pyrrolidinopyridine (0.4 g) and t-butanol (1.74 g) in DCM (120 ml) was stirred at room temperature, under nitrogen, for 4 h. The mixture was left to stand for 18 h, then ER (150 ml) was added and the mixture was filtered and washed with ER. The filtrate was evaporated in vacuo to leave a yellow suspension. F.C.C. (A) eluting with hexane gave a white semisolid, which was further chromatographed eluting with hexane, then 1% ER in hexane, and finally 2% gave a colorless liquid. Vacuum distillation by Kugelrohr at 0.4 mmHg and at 140°-150° gave the title compound as a colorless oil (0.55 g). T.l.c. (A) hexane:ER (3:1) Rf 0.68.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2.[N+:19]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O)([O-:21])=[O:20]>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[N+:19]([O-:21])=[O:20]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CC(=O)N2
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Cc1ccccc1[N+](=O)[O-])C(=O)N2
Yield: 33 %

Procedure:
Starting from 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-2H-indol-2-one and 2 nitro benzaldehyde and following the method described in Example 10, the desired compound was obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[C:9]([OH:11])=[O:10].C([O-])(O)=O.[Na+]>C(O)(=O)C>[F:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([N+:1]([O-:4])=[O:2])=[C:8]([CH:7]=1)[C:9]([OH:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(F)cc(C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(F)cc(C(=O)O)c1[N+](=O)[O-]
Temperature: 55 °C
Yield: 66 %

Procedure:
To a solution of fuming nitric acid (18 mL) and glacial acetic acid (36 mL) preheated to 55° C. was added 3-fluoro-5-methoxybenzoic acid (3.00 g, 17.63 mmol) portion wise over 5 min. The mixture was maintained at 55° C. for an additional 90 min. The reaction was cooled to ambient temperature and poured onto ice-water (200 mL). The pH of the solution was adjusted to 2 using aqueous NaHCO3 solution. The precipitate formed was filtered and washed with hexanes (100 mL) to afford 5-fluoro-3-methoxy-2-nitrobenzoic acid (2.52 g, 66%) as a white solid. 1H NMR and MS consistent.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:14][C:15]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][NH:35][CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][N:35]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:22][CH2:23]1.[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: CN(C)C(=O)Cl
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CNCC4)CC2)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CN(C(=O)N(C)C)CC4)CC2)c(F)c1
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (4.9 mg, 0.046 mmol) was added to a solution of 2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (12.1 mg, 0.023 mmol) and triethylamine (10 μL, 0.069 mmol) in DCM (230 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (12.1 mg, 88%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.27-1.32 (m, 6H), 1.89-1.99 (m, 2H), 2.06-2.15 (m, 2H), 2.81 (s, 2H), 2.91 (s, 6H), 3.00-3.09 (m, 2H), 3.39-3.46 (m, 2H), 3.55 (t, J=5.8 Hz, 2H), 3.75 (s, 3H), 4.13 (quin, J=6.4 Hz, 1H), 4.30 (s, 2H), 4.34-4.40 (m, 1H), 6.67 (ddd, J=8.9, 3.0, 1.5 Hz, 1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 487.4.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O>O1CCOCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][C:19]=3[C:10]=2[CH:9]=1
Reactant: CN1CCCCC1=O
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sulfuric acid is added to a solution of 4-fluorophenyl hydrazine hydrochloride (1 equiv.) in dioxane and stirred for 5 min. at RT. N-Methyl piperidone (0.76-1.4 equiv.) is added and the mixture is heated at 80° C. for 2 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The reaction mixture is extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]2[CH2:9][CH:4]([CH2:5][CH2:6][C@@H:7]2[NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:3]1.[Li+].[BH4-]>C1COCC1>[OH:3][C@@H:4]1[CH2:5][CH2:6][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:8]([CH2:2][OH:1])[CH2:9]1
Reactant: O=C(N[C@H]1CCC2C[C@H]1C(=O)O2)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@@H](O)C[C@H]1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sample of benzyl (1R,2S,SR)-7-oxo-6-oxa-bicyclo[3.2.1]octan-2-ylcarbamate (2.8 g) was dissolved in anhydrous THF prior to the addition of LiBH4 (0.44 g) in one portion. The reaction mixture was stirred at rt overnight. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with brine and dried (MgSO4). Filtered, concentrated and chromatographed to get benzyl (1S,2R,4R)-4-hydroxy-2-(hydroxymethyl)cyclohexylcarbamate as a white foamy solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([NH:1][C:32](=[O:34])[CH3:33])=[C:3]([C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1c(C(=O)C(C)(C)C)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.050 g (0.106 mmol) of the product from Example 17 in CH2Cl2 (1 mL) at 0° C. was treated with acetyl chloride (8 μL; 0.106 mmol) followed by triethylamine (15 μL; 0.106 mmol). After the addition, the reaction mixture was warmed to RT and stirred for 1 hour. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate-hexane gradient) gave the title compound. HPLC/MS: 515.0 (M+1), 517.0 (M+3); Rt=4.94 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:18][NH:19]C(OCC2C=CC=CC=2)=O)[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[BrH:30].C(O)(=O)C.CCCCCC.C(OC(C)C)(C)C>C(Cl)(Cl)Cl.C(OCC)C>[BrH:30].[BrH:30].[CH2:1]([O:3][C:4]([C:6]1([CH2:18][NH2:19])[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CNC(=O)OCc2ccccc2)CCN(c2ccncc2)CC1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCOC(=O)C1(CN)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-benzyloxycarbonylaminomethyl-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (331 mg) in chloroform (0.5 ml) was added 25% hydrogen bromide-acetic acid (2 ml), and the mixture was stirred at room temperature for 10 min. After completion of the reaction, hexane, diisopropyl ether and diethyl ether were added and the supernatant was removed. Then, dimethylformamide (1 ml) was added and the resultant solid was collected by filtration, and washed with diethyl ether and dried under reduced pressure to give the title compound (423 mg).
Reaction SMILES: [Li]CCCC.CCCCCC.[CH:12]1[C:24]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.Cl[Si:26]([CH:29]1[C:37]2[C:32](=[C:33]([CH3:39])[CH:34]=[CH:35][C:36]=2[CH3:38])[CH:31]=[C:30]1[CH3:40])([CH3:28])[CH3:27].[Li]>CCOCC.C1COCC1.C1(C)C=CC=CC=1>[CH3:40][C:30]1[CH:29]([Si:26]([CH:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:24]2=[CH:12][CH:13]=[CH:14][CH:15]=3)([CH3:28])[CH3:27])[C:37]2[C:32]([CH:31]=1)=[C:33]([CH3:39])[CH:34]=[CH:35][C:36]=2[CH3:38]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC1=Cc2c(C)ccc(C)c2C1[Si](C)(C)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1=Cc2c(C)ccc(C)c2C1[Si](C)(C)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.1 %

Procedure:
A 2.5 M n-BuLi solution in hexane (16.80 mL, 42.00 mmol, n-BuLi:fluorene=1.04:1) was added dropwise at 0° C. under stirring to a solution of 6.70 g of fluorene (40.31 mmol) in 100 ml of Et2O in a 500 mL 3-necked round flask. The resulting orange solution was allowed to warm up to room temperature and stirred for 1 h. A solution of chloro(2,4,7-trimethylindenyl)dimethylsilane (10.05 g, 40.06 mmol) in 20 mL of THF was cooled to 0° C. and slowly added to the lithium salt solution, also previously cooled to 0° C. At the end of the addition an orange-brown suspension was obtained. The latter was allowed to warm up to room temperature and stirred for 1.5 h. Then the reaction mixture was evaporated under reduced pressure to give a brown sticky solid, which was treated at r.t. with 150 mL of toluene and finally filtered to remove LiCl. The filtrate was dried in vacuo to give 16.48 g of a reddish oil, whose 1H NMR showed it to be the target compound contaminated by minor amounts of not identified by-products (crude yield quantitative). The product was used as such in the next step without further purification.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:13])([CH3:12])[CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[OH:14].[OH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][CH:17]=1.B(O)(O)O>ClC1C=CC=CC=1Cl>[CH3:12][C:9]([C:7]1[CH:6]=[CH:5][C:4]2[O:14][C:20]([C:19]3[CH:23]=[CH:24][C:16]([OH:15])=[CH:17][CH:18]=3)=[N:2][C:3]=2[CH:8]=1)([CH3:13])[CH2:10][CH3:11]
Reactant: CCC(C)(C)c1ccc(O)c(N)c1
Reactant: O=C(O)c1ccc(O)cc1
Agent: OB(O)O
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CCC(C)(C)c1ccc2oc(-c3ccc(O)cc3)nc2c1
Yield: 81.5 %

Procedure:
A 350 ml three necked reaction flask, equipped with a mechanical stirrer, a thermometer a “wood metal” heating bath and a reflux condenser combined with a water separator were charged with 25.1 g (140 mmol) of 2-amino-4-(1,1-dimethyl-propyl)-phenol (see above), 19.3 g (140 mmol) of 4-hydroxy benzoic acid and 1.5 g of boric acid suspended in 140 ml of 1,2-dichlorobenzene under nitrogen atmosphere. This mixture was refluxed until two equivalents of water had separated (about 4 hours). When cold, 50 ml of diisopropylether were added and this mixture was filtered and the crystalline product was washed with diisopropylether and pentane and dried. 32.1 g (81%) of the product were obtained. M.p. 236-237° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[N:4][O:5][C:6]=1[N:7]([CH2:19][O:20][CH3:21])[S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([Cl:18])=[O:17])(=[O:10])=[O:9].Cl[C:24]1C(C)=NOC=1N(COC)S(C1C=C(C)SC=1C(O)=O)(=O)=O>>[Cl:1][C:2]1[C:3]([CH3:22])=[N:4][O:5][C:6]=1[N:7]([CH2:19][O:20][CH3:21])[S:8]([C:11]1[CH:15]=[C:14]([CH3:24])[S:13][C:12]=1[C:16]([Cl:18])=[O:17])(=[O:9])=[O:10]
Reactant: COCN(c1onc(C)c1Cl)S(=O)(=O)c1cc(C)sc1C(=O)O
Reactant: COCN(c1onc(C)c1Cl)S(=O)(=O)c1ccsc1C(=O)Cl
Product: COCN(c1onc(C)c1Cl)S(=O)(=O)c1cc(C)sc1C(=O)Cl

Procedure:
N-(4-Chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid chloride was synthesized in the same fashion as for N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarbonyl chloride (Example 51) except that N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid was used instead of N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarboxylic acid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].CS(O[CH2:13][CH:14]([N:16]1[C:29]2[CH:28]=[C:27]([C:30]#[N:31])[CH:26]=[CH:25][C:24]=2[S:23][C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])(=O)=O>C(O)C>[OH:7][CH2:6][C@H:2]1[CH2:3][CH2:4][CH2:5][N:1]1[CH2:15][CH:14]([N:16]1[C:29]2[CH:28]=[C:27]([C:30]#[N:31])[CH:26]=[CH:25][C:24]=2[S:23][C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:13]
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: OC[C@H]1CCCN1
Solvent: CCO
Product: CC(CN1CCC[C@@H]1CO)N1c2ccccc2Sc2ccc(C#N)cc21

Procedure:
(R)-(-)-2-Pyrrolidinylmethanol (50 g) is added to a suspension of (2RS)-2-(2-cyano-10-phenothiazinyl)propyl methanesulphonate (89.1 g) in absolute ethanol (2000 cc). The mixture is brought to reflux for 23 hours. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa). The residue is diluted with ethyl acetate (350 cc) and filtered, and the filtrate is washed with distilled water (150 cc) and saturated sodium chloride solution (2×100 cc). After settling has taken place, the organic phase is extracted with hydrochloric acid (350 cc) in 3N solution. The acidic aqueous extracts are extracted with ethyl acetate (200 cc) and then alkalinized with concentrated sodium hydroxide and re-extracted with ethyl acetate (3×200 cc). The organic phase is washed with distilled water (2×200 cc) and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give a residue which is purified by chromatography on a column (height: 46 cm; diameter: 8.5 cm) of silica gel (0.2-0.06 mm), eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 80:20 (12 liters) and 70:30 (30 liters), collecting 250-cc fractions. The first 12 liters are discarded and fractions 61 to 118 are combined and evaporated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbonitrile, L series (11.0 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][N:6](COC)[C:5](=[O:12])[C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[CH3:28])=[CH:15][CH:14]=1.Cl.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[N:7][NH:6][C:5](=[O:12])[C:4]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[CH3:28])=[CH:17][CH:18]=1
Reactant: COCn1ncc(OC)c(-c2ccc(OCCCN3CCC[C@H]3C)cc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cn[nH]c(=O)c1-c1ccc(OCCCN2CCC[C@H]2C)cc1
Temperature: 25 °C
Yield: 37 %

Procedure:
To a round-bottom flask was added example 231 (5-Methoxy-2-methoxymethyl-4-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one) (1.07 g, 2.76 mmol), methanol (10 mL), and concentrated HCl solution (10 mL). The reaction was heated to reflux for 3 days. After cooled to room temperature, the reaction was neutralized with 10 N NaOH then 5% NaOH solution to pH 7. The reaction was concentrated and the residue was washed with CH2Cl2 (100 mL). The CH2Cl2 layer was concentrated. Purification by column chromatography (15% MeOH in CH2Cl2) to give 350 mg (37%) of 5-methoxy-4-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one. The product was converted to its hydrochloride salt. Mp 135-140. MS m/z 344 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[C:17]([CH3:18])=[N:16][N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[OH:25])=[CH:11][C:10]([CH3:26])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[C:14](=[O:25])[N:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:16]([CH3:27])[C:17]=2[CH3:18])=[CH:11][C:10]([CH3:26])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(Cc2ccccc2)n1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(-c2c(C)n(C)n(-c3ccccc3)c2=O)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
To 2-benzyl-5,5′-dimethyl-2′-phenyl-2H,2′H-[3,4′]bipyrazolyl-3′-ol (Example 36, 0.200 g, 0.58 mmol) in DMF add cesium carbonate (0.944 g, 2.90 mmol), and then iodomethane (0.823 g, 5.8 mmol). Stir this mixture at room temperature overnight. Dilute the reaction mixture with ethyl acetate, wash with water (25 ml×5) and dry (sodium sulfate). Chromatograph on silica gel, eluting with 50-100% ethyl acetate/heptane to provide 0.045 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:21])[CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:18](=[O:19])[CH2:17][C:16](=[O:21])[NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=3)=[CH:4][CH:3]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Nc1ccccc1Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C1CC(=O)N(c2ccc(Cl)cc2)c2ccccc2N1
Yield: 60.7 %

Procedure:
To a stirred refluxing solution of N1-(4-chlorophenyl)benzene-1,2-diamine (100.0 mg, 0.46 mmol) in toluene (20 mL) was added dropwise a solution of malonyl dichloride (65.00 mg, 0.46 mmol). After addition was completed, the reaction mixture was refluxed for 1 h. The solvent was removed in vacuo, the mixture was stirred with water (20 mL), extracted with DCM (10 mL*3), and then was purified by Prep-TLC (DCM:MeOH=30:1) to give 1-(4-chlorophenyl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (80.00 mg, 60%) as a white solid. LRMS (M+H+) m/z: calcd 286.05. found 286.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][NH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:48]=[C:47]([O:49][CH3:50])[C:41]2[O:42][CH2:43][CH2:44][CH2:45][O:46][C:40]=2[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:50][O:49][C:47]1[C:41]2[O:42][CH2:43][CH2:44][CH2:45][O:46][C:40]=2[CH:39]=[C:38]([CH:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:28][CH:27]=2)[C:23]2[NH:22][C:21](=[O:20])[N:10]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[N:11]=2)[CH:48]=1
Reactant: NNc1ncccc1[N+](=O)[O-]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1)OCCCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)cc2c1OCCCO2
Temperature: 85 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
After adding 37.3 mg of (3-nitropyridin-2-yl)hydrazine and 37 μl of triethylamine to a solution of 109 mg of [2-(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (30c)) in 5 ml of DMF under a nitrogen atmosphere, the mixture was heated at 85° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 20 ml of a methanol:THF=1:1 mixed solvent, 83 mg of sodium cyanotrihydroborate and 32 μl of acetic acid were added and the mixture was stirred at room temperature for 24 hours. After adding 100 ml of ethyl acetate and 50 ml of water, filtration was performed with celite. The aqueous layer was extracted with 50 ml of ethyl acetate, and then the organic layers were combined and dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate (1:40)) to give the title compound (59 mg) as a light yellow solid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].C([O-])(=O)C.[Na+].[OH-].[Na+]>O>[CH2:34]([O:33][C:31]([N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:32])[CH3:35]
Reactant: C1CNCCNC1
Reactant: CCOC(=O)Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Solvent: O
Product: CCOC(=O)N1CCCNCC1

Procedure:
Combine [1,4]diazepane (33.9 g, 340 mmol) and water (250 mL). Add methyl orange and adjust the pH using 3 M aqueous hydrochloric acid solution until the indicator turns red. Add dropwise, ethyl chloroformate (38 mL, 400 mmol) over about 2.5 hours while maintaining the pH using first aqueous sodium acetate and then aqueous sodium hydroxide solution. After the addition is complete adjust the pH to 8 using aqueous sodium hydroxide solution and extract three times with diethyl ether. Discard the organic extracts and saturate the aqueous layer with potassium carbonate. Extract three times with diethyl ether. Combined organic layers from the second extraction, dry the over Na2SO4, filter, and evaporate in vacuo to give a 1-ethoxycarbonyl[1,4]diazepane.