Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:22])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][OH:21])[N:18]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.C(Cl)Cl.CC(C)=O>[CH2:23]([O:21][CH2:20][CH2:19][C:17]1[N:18]=[C:14]([NH:13][S:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=2[CH3:22])(=[O:11])=[O:12])[S:15][CH:16]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCO)cs1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCOCc2ccccc2)cs1
Reaction time: 0.25 h

Procedure:
Sodium hydride (95% dry, 76 mg, 3.00 mmol) was added to a stirred solution of EXAMPLE 181A (400 mg, 1.20 mmol) in THF (10 mL) at room temperature. After stirring for 15 min. the mixture was treated with benzyl bromide (226 mg, 1.32 mmol). After 2 h at 50° C. additional sodium hydride (60 mg, 2.40 mmol) and benzyl bromide (142 mg, 1.20 mmol) were added in two equal portions under a period of 2 h. The reaction was quenched by adding 1M HCl (3 mL) at room temperature. The mixture was extracted with DCM and dried (Sodium sulfate). Evaporation of the solvent gave a residue which was purified by flash chromatography on silica gel eluting with 5% acetone in DCM giving (105 mg, 0.25 mmol, 21%) which solidified on standing: MS (Ionspray, [M+H]+) m/z 322. Anal. Calcd. (found) for C19H19ClN2O3S2.0.5 CH2Cl2: C, 50.3 (50.7)%; H, 4.3 (4.1)%; N, 6.0 (5.9)%.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[C:8](=S)=[S:9].IC.[CH3:13][S:14]([CH3:16])=O>O>[CH3:13][S:14][C:16](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[S:9][CH3:8]
Reactant: S=C=S
Reactant: CS(C)=O
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CSC(SC)=C(C#N)C#N
Temperature: 15 °C
Reaction time: 0.17 h

Procedure:
Add malononitrile (50.0 g, 757 mmol) to dry DMSO (600 mL), mechanically stir, cool to 15° C., and place under nitrogen. Add NaH (60%, 40 g, 1.00 mol) in small portions over 25 min keeping the internal temperature <25° C. and stir mixture. After 10 min, slowly add carbon disulfide (45.5 mL, 757 mmol) over 20 min at the same temperature. Stir at room temperature for 2.5 h then add additional NaH (60%, 29.6 g, 0.74 mol) while keeping the temperature constant with external cooling. Stir for 1.5 h at rt then cool to 15° C. Add iodomethane (103.7 mL, 1.67 mol) over 15 min. Stir resulting mixture overnight then pour into water (2.8 L). Stir the resulting dark orange precipitate for 15 min then collect by filtration, wash with water, partially air-dry, and wash with hexanes. Air-dry the tan powder to a constant weight (103 g) then recrystallize from 2-propanol. Filter solid, wash with cold 2-propanol and hexanes, then dry to afford the title compound: 1H NMR (DMSO-d6): δ 2.78 (s, 6H); 13C NMR (DMSO-d6): δ 186.0, 113.3, 74.2, 18.9.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[C:45]1[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc(C2CCN(C(=O)c3ccccc3)CC2)cc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-[4-(piperidin-4-yl)phenyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.29 (s, 1H), 7.47-7.50 (m, 2H), 7.41-7.47 (m, 5H), 7.34-7.38 (m, 2H), 7.29-7.33 (m, 2H), 7.16-7.18 (m, 2H), 4.75-4.76 (bs, 4H), 4.54-4.64 (m, 1H), 3.57-3.74 (m, 1H), 3.02-3.21 (m, 1H), 2.79-2.93 (m, 1H), 2.75 (tt, J=11.9, 3.4 Hz, 1H), 1.68-1.88 (m, 2H), 1.54-1.63 (m, 2H); MS (ESI(−)) m/e 424 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36](Cl)=[O:37]>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:23][CH:24]=1)=[O:37]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(N)cc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c2ccccc21
Yield: 79.8 %

Procedure:
In a dry reaction vessel, ethyl 2-[3-(4-aminobenzyl)-2-methyl-1H-indol-1-yl]acetate (1.0 g, 3.11 mmol) was added, and dissolved in 15 mL dichloromethane. Triethylamine (1.3 mL, 9.3 mmol) was added, and in an ice bath a dichloromethane solution dissolving 3,4-dichlorobenzoyl chloride (0.652 g, 3.11 mmol) was added slowly. After completion of dropwise addition, it was reacted in an ice bath for 4 h, and filtered. An aqueous solution of sodium bicarbonate was added, extracted with dichloromethane, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 1.23 g, at a yield of 79.7%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([Cl:19])=[O:18]>>[ClH:19].[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH3:13])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)Nc1cccc2c1CCN(C)C2
Product: Cl

Procedure:
The title compound was prepared in an analogous fashion to Example 2 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 2-methoxybenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>S(Cl)(Cl)=O.O1CCCC1>[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[N:3][C:2]([Cl:1])=[CH:11][CH:10]=3)=[O:14])=[CH:37][CH:36]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1cnc2ccc(Cl)nc2c1Nc1cccc(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)c2cnc3ccc(Cl)nc3c2Nc2cccc(C(F)(F)F)c2)cc1
Temperature: 75 °C
Yield: 94.3 %

Procedure:
6-chloro-4-(3-(trifluoromethyl)phenylamino)-1,5-naphthyridine-3-carboxylic acid (3.6 g, 9.8 mmol) was suspended in 50 mL sulfinyl chloride. The resulting mixture was heated under stirring to 75° C. and reacted for 4 hrs while keeping at the same temperature. The reaction was naturally cooled to room temperature, and concentrated to obtain a yellow solid. The resulting solid was dispersed in 100 mL tetrahydrofuran. To the resulting mixture was added dropwise a mixture of triethylamine (3.03 g, 30 mmol) and para-methoxybenzylamine (1.6 g, 13 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 hrs, and rotary-evaporated to remove the solvent. To the residue was added 300 mL water. The resulting mixture was filtered by suction. The filter cake was washed with ethyl acetate and petroleum ether (volume ratio 1/10, 100 mL) and dried to obtain a pale yellow solid of N-(4-methoxybenzyl)-6-chloro-4-(3-(trifluoromethyl)phenylamino)-1,5-naphthyridine-3-carboxamide (4.5 g).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:22]=O)=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:24][NH2:25].[BH4-].[Na+].CO>O1CCCC1>[F:1][C:2]1[C:3]([CH2:22][NH:25][CH3:24])=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN
Reactant: O=Cc1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
4-Fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.27 g) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution (0.8 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hr. Sodium borohydride (91 mg) and methanol (7 mL) were added, and the mixture was stirred at the same temperature for further 30 min. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane-ethyl acetate=19:1→0:1). The above-mentioned operation was repeated to give the title compound (0.22 g, yield 39%) as a colorless solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH3:16])=[O:14])[C:9]([CH3:18])([CH3:17])[CH2:8]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:17][C:9]1([CH3:18])[CH2:8][CH:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][CH2:11][CH:10]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CCC(O)CC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(OS(C)(=O)=O)CC1(C)C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (1.69 mL, 21.7 mmol) was added at −20° C. to a solution of racemic methyl 4-hydroxy-2,2-dimethylcyclohexanecarboxylate (3.11 g, 16.7 mmol) and triethylamine (4.65 mL, 33.4 mmol) in dichloromethane (67 mL). The reaction was stirred for 3 hours. Saturated aqueous sodium bicarbonate was added to the mixture and extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 2,2-dimethyl-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate. 1H NMR (500 MHz, CDCl3) δ 4.92-4.72 (m, 1H), 3.64 (s, 3H), 2.99 (s, 3H), 2.29-2.15 (m, 1H), 2.15-2.00 (m, 1H), 1.99-1.87 (m, 1H), 1.83-1.71 (m, 2H), 1.63-1.59 (m, 1H), 1.49-1.32 (m, 1H), 1.01 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[Br:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CCCCCC.CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:30][C:29]1[CH:32]=[CH:33][C:26]([Br:25])=[CH:27][CH:28]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)c1cc(C)cc(C)c1N(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 86.4 %

Procedure:
In the same manner as described in Example 9, 0.699 g (2.0 mmol) of the product of Example 62 and 0.6 g (2.4 mmol) of p-bromobenzyl bromide provided 0.896 g (86%) of the desired product as a white solid after trituration with hexane/ether. Electrospray Mass Spec 518.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[O:3][C:4]1[CH:36]=[CH:35][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([NH:17][C:18](=[O:24])[CH2:19][CH2:20][C:21](O)=[O:22])[CH2:14][N:13]2[C:12](=[O:25])[N:11]([C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:10]3=[O:34])=[CH:6][CH:5]=1.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(Cl)CCl>[F:37][C:2]([F:38])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([NH:17][C:18](=[O:24])[CH2:19][CH2:20][C:21]([N:43]4[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]4)=[O:22])[CH2:14][N:13]2[C:12](=[O:25])[N:11]([C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:10]3=[O:34])=[CH:35][CH:36]=1
Reactant: O=C(O)CCC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)CCC(=O)N[C@@H]2CN3C(=O)N(c4cc(Cl)nc(Cl)c4)C(=O)[C@@]3(Cc3ccc(OC(F)(F)F)cc3)C2)CC1
Reaction time: 8 h

Procedure:
To a solution of the compound from Example 66 (0.12 g) in THF (5 mL) was added N-methyl piperazine (50 μL), EDC (0.90 g), HOBt (0.090 g), and DIEA (0.10 mL). After stirring overnight the reaction mixture was concentrated. The residue was dissolved in EtOAc, washed with water and brine, dried (Na2SO4), filtered, concentrated and purified by chromatography (silica gel: 95:5 CH2Cl2: MeOH, Chromatotron) to afford the titled compound (0.10 g). MS (m/z) 657 [MH+]. mp 70° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:10][C:11](=[O:33])[CH:12]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:20]C(OC(C)(C)C)=O)=[CH:18][CH:19]=1)[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11](=[O:33])[CH:12]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=1)[CH3:9]
Reactant: CCOC(=O)C(CSC(C)=O)Cc1ccc(NC(=O)OC(C)(C)C)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CSC(C)=O)Cc1ccc(N)nc1
Reaction time: 1 h
Yield: 141.7 %

Procedure:
TFA (0.5 mL) was added to a solution of 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylaminopyridin-3-yl)-propionic acid ethyl ester (100 mg, 0.26 mmol) in methylene chloride (2 mL) under argon. The solution was stirred for 60 min and concentrated under reduced pressure to give crude 2-acetylsulfanylmethyl-3-(6-amino-pyridin-3-yl)-propionic acid ethyl ester (104 mg, 100%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([Cl:22])[C:12]=1[C:13](O)=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([Cl:22])[C:12]=1[C:13]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:14]
Reactant: c1cc2[nH]ccc2cn1
Reactant: O=C(O)c1c(Cl)cc(CO)cc1Cl
Product: O=C(c1c(Cl)cc(CO)cc1Cl)n1ccc2cnccc21

Procedure:
[2,6-Dichloro-4-(hydroxymethyl)phenyl](1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (Compound No. 90) was synthesized from N-(1H-pyrrolo[3,2-c]pyridine and 2,6-dichloro-4-(hydroxymethyl)benzoic acid.
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1.[CH3:22][O:23][CH2:24][CH2:25]Br>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]=[C:9]2[N:14]([CH2:25][CH2:24][O:23][CH3:22])[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[N:19][C:11]=3[S:10]2)=[CH:6][CH:5]=1
Reactant: COCCBr
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COCCn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Reaction time: 0.07 h
Yield: 26.8 %

Procedure:
In an atmosphere of argon, a mixture of 26 mg (3.3 mmol) of lithium hydride and 5 ml of DMF was put in a 100 ml flask. To the flask was then connected a dropping funnel which contained 800 mg (2.8 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 10 ml of DMF. The solution of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was then added dropwise to the aforementioned mixture with stirring in 4 minutes. The mixture was further stirred for 50 minutes. To the mixture was then added a mixture of 576 mg of 2-bromoethyl methyl ether and 2 ml of DMF. The mixture was then stirred for 21 hours. After the termination of reaction, the mixture was concentrated under reduced pressure. The resulting residue was then extracted with water and ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: 1/2 mixture of ethyl acetate and normal hexane). As a result, 261 mg of 2-[(4-chlorophenyl)imino]-2,3-dihydro-3-(2-methoxyethyl)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 79 mg of 2-[N-(4-chlorophenyl)-N-(2-methoxyethyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:34]=1[CH2:35]Br>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:35][C:34]3[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:33]=3[F:32])[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Solvent: CC#N
Solvent: O
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2cc(F)ccc2F)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 2,5-difluorobenzyl bromide and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29-7.37 (m, 1H) 6.97-7.09 (m, 3H) 6.87-6.96 (m, 1H) 6.68-6.80 (m, 1H) 5.92-6.02 (m, 1H) 5.73-5.90 (m, 2H) 5.13-5.45 (m, 1H) 4.13-4.27 (m, 2H) 3.62-3.74 (m, 3H) 2.59-2.78 (m, 2H) 2.05-2.17 (m, 2H) 1.91-2.05 (m, 3H) 0.97-1.22 (m, 9H); LCMS (m/z) ES+=551 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][C:22]#[N:23])=[CH:15][CH:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].C([Sn]([N:44]=[N+:45]=[N-:46])(CCCC)CCCC)CCC>C1COCC1.CCOCC.Cl>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][C:22]3[NH:46][N:45]=[N:44][N:23]=3)=[CH:15][CH:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)CCC#N)cc2)ccc(C(C)=O)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1c(OCCCSc2ccc(C(=O)CCc3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The nitrile from Example 40, Step E, (1.0 g, 2.35 mmole) and tri-n-butyltin azide (1.0 g, 3.0 mmole) in dry THF (20 ml) were stirred at 70° for 48 hours, and then heated at reflux for 24 hours. The reaction mixture was cooled to room temperature, diluted with ether (20 ml) and concentrated HCl was added. After 1 hour, the solution was filtered, the solid was washed with ether and dried to yield the title compound.
Reaction SMILES: [NH3:1].C(=O)([O-])[NH2:3].[NH4+].[NH2:7][C:8]([NH2:10])=[O:9].[S:11](=[O:15])(=[O:14])([OH:13])[OH:12]>>[NH2:7][C:8]([NH2:10])=[O:9].[S:11]([O-:15])([O-:14])(=[O:13])=[O:12].[NH4+:3].[NH4+:1]
Reactant: NC(=O)[O-]
Reactant: N
Reactant: O=S(=O)(O)O
Agent: NC(N)=O
Agent: [NH4+]
Product: O=S(=O)([O-])[O-]

Procedure:
WO 01/51429 relates to a method for producing a fertilizer containing ammonium sulphate and urea. An aqueous urea solution is provided which, with regard to the total weight of the solution, contains 0.1 to 50 wt. % of free ammonia and/or of ammonia that is bound in the form of ammonium carbamate. Said aqueous urea solution is reacted with sulphuric acid and, optionally, with ammonia at a temperature ranging from 25 to 250° C. and at a pressure ranging from 0.1 to 250 bar. A urea-ammonium sulphate solution or suspension is formed in quantities that result in a weight ratio of ammonium sulphate to urea in this urea-ammonium sulphate solution or suspension that ranges from 10:90 up to 65:35. Carbon dioxide and ammonia expelled under these conditions are returned to the urea synthesis. Afterwards, this urea-ammonium sulphate solution or suspension is subjected to a subsequent processing in order to produce solid or liquid fertilizers.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]([C:18]([OH:20])=O)=[C:4]1[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:5]1=[N:6]2.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25].C(N(CC)CC)C>O=S(Cl)Cl.C(Cl)Cl>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH:25][C:18]([C:3]1[C:2]2[C:7](=[CH:8][CH:9]=[CH:10][CH:1]=2)[N:6]=[C:5]2[C:11]3[C:16]([NH:17][C:4]=12)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:20]
Reactant: O=C(O)c1c2ccccc2nc2c1[nH]c1ccccc12
Reactant: CN(C)CCN
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)CCNC(=O)c1c2ccccc2nc2c1[nH]c1ccccc12
Reaction time: 14 h
Yield: 60.2 %

Procedure:
10H-indolo[3,2-b]quinoline-11-carboxylic acid (0.5 g, 1.9 mmol) was dissolved in 20 ml of refluxing SOCl2, After 6 hours a clear solution was obtained, and all volatiles were removed in vacuo. The crude acid chloride was suspended in 10 ml of CH2Cl2. A solution of N,N-dimethylethylendiamine (0.2 mL, 2.26 mmol) and triethylamine (2.2 ml) in 10 ml of CH2Cl2 was added at room temperature, and the mixture was stirred for 14 hours. The organic phase was washed (NaHCO3, brine) and dried (MgSO4). Removal of the solvent and purification by chromatography on alumina (CH2Cl2/MeOH, 90:10) yielded the desired compound (0.38 g, 61%) as a solid. m. p. 175-176° C. 1H-NMR [MeOD, _, ppm]: 8.16 (d, J=7.8 Hz, 1H), 7.92 (m, 2H), 7.35-7.20 (m, 3H), 7.04 (m, 2H), 3.62 (m, 2H, CH2NO), 2.55 (m, 2H, CH2N(CH3)2), 2.29 (s, 6H, N(CH3)j. MS (EI, m/z) 277 (M++1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.C(Cl)Cl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:17])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A stirred solution of 20.0 grams (0.105 mole) of 4-trifluoromethylbenzoic acid and four drops of dimethylformamide in 300 mL of methylene chloride was cooled to 0°-10° C., and 14.7 grams (0.116 mole) of oxalyl chloride was added. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 18 hours. The reaction mixture was then concentrated under reduced pressure, yielding 21.9 grams of 4-trifluoromethylbenzoyl chloride as a semi-solid. The reaction was repeated.