Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH2:4]O.C1OC2C=CC(C[Cl:19])=CC=2O1.S(Cl)(Cl)=O>CCOCC>[CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH2:4][Cl:19]
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: COc1ccc(CO)c(C)c1C
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(CCl)c(C)c1C

Procedure:
1 g (6.016 mmol) of 2,3-dimethyl-4-methoxybenzyl alcohol (Aldrich, Steinheim, FRG) and 4.8 g of diisopropylaminomethylpolystyrene (polyhunig base, see Ex. 44a) in 21 ml of abs. ether are treated dropwise, at from 0° C. to 5° C. and over the space of approximately 25 min, with 0.482 ml of thionyl chloride. After the reaction has ended, the mixture is filtered with suction and the solvent and the excess reagent are removed. The residue, which is the desired title compound, is subjected, without purification, to further processing. TLC Rf (hexane:ethyl acetate 4:1)=0.59. IR(CH2Cl2) inter alia: 1599, 1485, 1466 und 1107 cm-1. 1H-NMR (200 MHz, CDCl3): 7.14 (d, 1H); 6.69 (d, 1H); 4.64 (s, 2H); 3.82, 2.34 and 2.18 (each s, each 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10](I)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH3:23])[O:22][CH2:21][CH2:20][O:19]4)=[CH:14][CH:13]=3)[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1.[Li][CH2:33][CH2:34]CC.C(I)C.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH2:33][CH3:34])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH3:23])[O:22][CH2:21][CH2:20][O:19]4)=[CH:14][CH:13]=3)[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(c2ccc(-c3c(I)c4nc(Br)cnc4n3COCC[Si](C)(C)C)cc2)OCCO1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: -75 °C
Reaction time: 0.08 h
Yield: 48.6 %

Procedure:
2-Bromo-7-iodo-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (17.5 g, 28.4 mmol) in THF (200 mL) was cooled to about −75° C. then n-BuLi (1.6 M in hexanes, 19.5 mL, 31.2 mmol) was added keeping the temperature between about −70 and −75° C. The mixture was stirred for about 5 min at about −75° C. The mixture was treated with EtI (6.2 mL, 77 mmol) then the temperature of the mixture was raised to about 15° C. over about 5 to 10 min. The mixture was stirred at about 20° C. for about 30 min then saturated aqueous NH4Cl (10 mL) was added. The mixture was stirred for about 15 min at about 20° C. then concentrated under reduced pressure. The material was partitioned between Et2O (200 mL) and water (100 mL) the layers were separated and then the aqueous layer was extracted with Et2O (100 mL). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was applied to a 120 g silica column and eluted with 9:1 heptane/EtOAc. The fractions largely free of impurities were collected. The impure fractions were combined and evaporated then a second 80 g silica column was run on this material with 9:1 heptane/EtOAc as an eluent to give a second lot of material largely free of impurities. The material from the two columns were combined then further purified by flash chromatography on a 220 g silica gel cartridge with a gradient of 0 to 10% EtOAc/heptane to give 2-bromo-7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (7.16 g, 49%): LC/MS (Table 2, Method g) Rt=2.0 min; MS m/z 518 (M+H)+.
Reaction SMILES: [K+].[CH:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH-:14])(=[O:13])=[O:12])=[N:9][CH:10]=1)([CH3:4])[CH3:3].[O-:15][Mn](=O)(=O)=O.[K+].Cl>O>[OH:15][C:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[N:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(O)c1ccc(S(N)(=O)=O)nc1
Temperature: 25 °C

Procedure:
To a solution of 5-isopropyl-pyridine-2-sulfonamide potassium salt (synthesis described in EP 0 799 209) in water (10 ml) were added 1.2 g of KMnO4 at RT and the mixture was then refluxed for 30 minutes. The mixture was cooled to RT, acidified with diluted HCl and the product was extracted into AcOEt. The organic layer was washed with washed with water, dried over Na2SO4 and concentrated in vacuo to give (5-(1-hydroxy-1-methyl-ethyl))-pyridine-2-sulfonic acid amide as yellow oil. EI mass spectrum, m/e 216 (M calculated for: C8H12N2O3S 216).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (13.9 g) obtained in Example 2 was suspended in dimethyl sulfoxide (500 ml), and to the suspension was added potassium carbonate (9.5 g), and the mixture was stirred at room temperature for 30 minutes. Ethyl bromoacetate (4.2 ml) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (500 ml) and precipitated crystals were recovered by filtration. The thus obtained crude crystals were purified by silica gel flash column chromatography (eluent: methylene chloride containing 3% methanol), and the crude product was re-precipitated from chloroform-hexane and recovered by filtration to obtain the title compound (9.0 g, 53%).
Reaction SMILES: [NH:1]1[C:10](=O)[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].P(Cl)(Cl)([Cl:14])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[NH2:3][C:2]1[N:4]=[C:5]2[C:9]([NH:8][CH:7]=[N:6]2)=[C:10]([Cl:14])[N:1]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: Nc1nc(Cl)c2[nH]cnc2n1
Reaction time: 1.17 h
Yield: 39 %

Procedure:
4.5 g (0.03 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd.), 7.5 g (0.045 mol) of tetraethylammonium chloride and 27.1 g (0.177 mol) of phosphorus oxychloride were added to 60 ml of acetonitrile, followed by stirring for 70 minutes under heating refluxing conditions. After cooling, the crystal was collected by filtration and suspended in 50 ml of water. This suspension was made alkaline with a 30% aqueous solution of sodium hydroxide and then adjusted to a pH of 7 with 1N hydrochloric acid. The resulting crystal was collected by filtration and dissolved in 50 ml of 25% aqueous ammonia with heating, and the insoluble substances were filtered out. The mother liquor was concentrated under reduced pressure to yield 2.0 g (0.012 mol) of a precipitating crystal of 2-amino-6-chloropurine (yield 39%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][C:3]=1[CH3:13].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:12][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:13])[CH:4]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CCCO)cc(C)c1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(CCCOS(C)(=O)=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cooled (0° C.) solution of 3-(4-bromo-3,5-dimethylphenyl)propan-1-ol (250 mg) and triethylamine (160 μL) in dichloromethane (2 mL) is added methanesulfonyl chloride (850 μL). The mixture is stirred for 12 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NaHCO3 solution and stirred vigorously for 30 minutes. The organic phase is separated, washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→50:50) to give the title compound. Yield: 235 mg; LC (method 8): tR=0.44 min; Mass spectrum (ESI+): m/z=343 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([CH:17]4[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)[C:14]=3[CH3:16])[C:10](=[O:28])[N:9]2[C:29]2[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[NH:19]1[CH2:18][CH:17]([N:13]2[C:14]([CH3:16])=[C:15]3[CH:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:9]([C:29]4[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=4)[C:10](=[O:28])[C:11]3=[N:12]2)[CH2:20]1
Reactant: Cc1cc(N2C(=O)c3nn(C4CN(C(=O)OC(C)(C)C)C4)c(C)c3C2c2ccc(Cl)cc2)cn(C)c1=O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3nn(C4CNC4)c(C)c3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared using an analogous procedure to that described in Step 138.2 using tert-butyl 3-(4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-6-oxo-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)azetidine-1-carboxylate (Step 138.1 b). tR: 0.61 min (LC-MS 2); ESI-MS: 424.1 [M+H]+ (LC-MS 2); Rf=0.05 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[N:6]=1)(=[O:3])[CH3:2].C(O[C@H:16]1[O:38][C@@H:37]([CH2:39][O:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:27]([O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:17]1[O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C.C[Si](N[Si](C)(C)C)(C)C.Cl[Si](C)(C)C.Cl[Sn](Cl)(Cl)Cl>CC#N>[C:19]([O:18][C@H:17]1[C@@H:27]([O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:37]([CH2:39][O:40][C:41](=[O:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[O:38][C@@H:16]1[N:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:6][C:7]1=[O:11])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: CC(=O)Nc1cc[nH]c(=O)n1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=O)Nc1ccn([C@H]2O[C@@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)c(=O)n1
Yield: 69.3 %

Procedure:
To a mixture of N4 -acetylcytosine (0.18 g, 1.19 mmol) and compound 2 (0.50 g, 0.99 mmol) in anhydrous MeCN (30 ml) were successively added HMDS (0.17 ml, 0.79 mmol), ClSiMe3 (0.10 ml, 0.79 mmol) and SnCl4 (0.14 ml, 1.19 mmol). The resulting clear solution was refluxed for one hour. Then the solvent was evaporated and the residue dissolved in EtOAc (100 ml), washed with NaHCO3 and H2O. After evaporation of the solvent the residue was purified on a silica gel column using EtOAc/petroleum ether (70%) to give pure 7 (0.41 g, 70%) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][C:3]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=2)[S:31]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:41][CH2:42][C:43]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=4[C:16]([CH3:19])([CH3:17])[CH3:18])=[CH:4][C:3]=3[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:44])=[CH:46][CH:47]=2)[S:31]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2C(C)(C)C)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2C(C)(C)C)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 77.6 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2-t-butyl-4-hydroxyphenoxy)phenyl]-N-methyl-carbamate (0.95 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.76 g), diethyl cyanophosphonate (0.44 g), triethylamine (0.27 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.24 g).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH3:14])[C:6]=1[CH:7]=[O:8]>O1CCOCC1>[Br:1][C:12]1[C:5]([O:4][CH3:3])=[C:6]([C:9]([S:13][CH3:14])=[CH:10][CH:11]=1)[CH:7]=[O:8]
Reactant: BrBr
Reactant: COc1cccc(SC)c1C=O
Solvent: C1COCCO1
Product: COc1c(Br)ccc(SC)c1C=O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Bromine (28.8 g, 0.18 mol) (dissolved in dioxane (500 ml)) was added dropwise to a solution of 2-methoxy-6-methylsulfanylbenzaldehyde (22 g, 0.12 mol) in dioxane (500 ml), and the mixture was stirred at 50° C. for 6 h. The mixture was then concentrated, the residue was taken up in CH2Cl2, and the mixture was washed with H2O , dried over MgSO4 and concentrated. The solid was recrystallized from diisopropyl ether.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:20])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.[C-:21]#[N:22].[K+].C(Cl)Cl>CN(C)C=O>[Cl:19][C:14]1[CH:13]=[C:12]([S:11][C:5]2[N:4]([CH3:20])[C:3]([CH2:2][C:21]#[N:22])=[N:7][C:6]=2[CH:8]([CH3:10])[CH3:9])[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: CC(C)c1nc(CCl)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1nc(CC#N)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 72.5 °C
Yield: 52.5 %

Procedure:
In 13.6 ml of dry dimethylformamide was dissolved 4.75 g (13.6 mmol)of 2-chloromethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole (28a)and 1.0 g of potassium cyanide (97.5%), and the mixture was stirred with heating at 70 to 75° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and to the residue, water was added. The mixture was extracted with diethyl ether, and the organic layer was washed with water 3 times and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was fractionated by silica gel chromatography (ethyl acetate:methylene chloride=1:9 to 4)to obtain 2.43 g of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]acetonitrile (Compound I-80a)(yield 53%). mp 103-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH2:36](I)[CH3:37]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:36][CH3:37])[CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCNCC1
Reactant: CCI
Product: CCN1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1-ethylpiperidin-4-yl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 113) and ethyl iodide at rt following General Procedure S.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[C:10](=[O:15])[NH:11][S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:9]2[C:10](=[O:15])[NH:11][S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1NS(=O)(=O)c2cccc([N+](=O)[O-])c21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2c1C(=O)NS2(=O)=O

Procedure:
3.0 gm (13 mmols) of 4-nitro-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide were dissolved in 100 ml of ethanol. The solution was hydrogenated with hydrogen, using a palladium/animal charcoal catalyst. After filtration, evaporation and recrystallization from ethanol 2.3 gm (89.5% of theory) of the amino compound were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:19]([CH3:37])[C:20]([C:35]#[N:36])=[C:21]2[C:25]=1[O:24][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[C:19]([CH3:37])[C:20]([C:35]#[N:36])=[C:21]3[C:25]=2[O:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[N:22]3)[CH2:4]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3ccccc3[N+](=O)[O-])nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3ccccc3[N+](=O)[O-])nc2c1C#N
Temperature: 100 °C
Yield: 53.3 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (90 μl, 0.71 mmol) and triethylamine (200 μl) were added to a dimethyl sulfoxide (5 ml) solution of 7-fluoro-5-methyl-2-(2-nitrophenyl)-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-210) (204 mg, 0.55 mmol). The system was purged with nitrogen, then sealed up, and heated at 100° C. for 1.5 hours. After cooling, the solvent was evaporated away under reduced pressure, then the resulting residue was dissolved in chloroform, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. Elution with a mixed solvent of chloroform/methanol (98:2, v/v) gave a main product. This was washed with a mixed solvent of isopropyl ether and ethanol, and the solid was collected by filtration to obtain the entitled compound (137 mg, 54%) as a yellow solid.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[CH:11][NH:12]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>CO>[CH3:17][N:18]1[CH2:19][CH:20]=[C:21]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:7][CH:8]=3)[NH:12][CH:11]=2)[CH2:22][CH2:23]1
Reactant: c1cc2ccc(N3CCCC3)cc2[nH]1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3cc(N4CCCC4)ccc23)CC1
Temperature: 72 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
6-(pyrrolidin-1-yl)-1H-indole (500 mg, 2.68 mmol) was added to a solution of potassium hydroxide (1.55 g, 27.62 mmol) in methanol (20 mL). 1-methylpiperidin-4-one (610 mg, 5.39 mmol) was then added, and the resulting solution was stirred at 72° C. overnight. The mixture was concentrated and the residue was poured into water (40 mL). After filtration, the filter cake was washed with water (1×50 mL) and diethylether (1×50 mL), to afford 400 mg (47.6%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(pyrrolidin-1-yl)-1H-indole as a white solid.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([NH2:13])[CH:2]=1.C(=O)(O)[O-].[Na+].[CH2:19](O)[CH3:20]>>[CH2:19]([O:10][C:9](=[O:11])[C@H:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([NH2:13])=[CH:2][CH:1]=1)[NH2:12])[CH3:20]
Reactant: Nc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)[C@@H](N)Cc1ccc(N)cc1
Temperature: 80 °C

Procedure:
About 40 g of dried L-4-amino phenylalanine was mixed with 1000 mL of ethanol. The reaction mass was dehydrated by distilling out about 20% of the ethanol added. To the dried reaction mixture about 300 g of dry hydrochloric acid gas was purged in. The reaction mass was warmed to about 80° C. and the reaction was promoted by removing condensation (water formed in the reaction) by distillation. The progress of the reaction was monitored by HPLC analysis. Upon completion of the esterification reaction, the reaction mass was neutralized with sodium bicarbonate and the precipitated inorganic salt was removed, isolated, washed with ethanol, and the filtrate was collected. The filtrate was concentrated by distillation and dehydrated to a thick mass. (the weight of reaction mass residue was 41 g; its purity 98%.)
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([F:20])(=[O:19])=[O:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](O)(=[O:26])[CH2:22][C:23](O)=[O:24].C(Cl)(=O)C>O>[CH:1]1([N:7]2[C:21](=[O:26])[CH2:22][C:23](=[O:24])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17]([F:20])(=[O:19])=[O:18])[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccccc1S(=O)(=O)F)NC1CCCCC1
Reactant: O=C(O)CC(=O)O
Solvent: O
Solvent: CC(=O)Cl
Product: O=C1CC(=O)N(C2CCCCC2)C(=O)N1c1ccccc1S(=O)(=O)F
Temperature: 25 °C

Procedure:
A mixture of N-cyclohexyl-N'-(2-fluorosulphonylphenyl) urea (300 g, 1 mole), malonic acid (156 g, 1 mole) and acetylchloride (427 ml, 6 moles) was refluxed for 4 hours with stirring, cooled to room temperature, poured into water (4.25 l) and stirred for 1 hour to decompose the excess of acetylchloride. Then the 1-cyclohexyl-3-(2-fluorosulphonylphenyl)barbituric acid formed was added with portions and with stirring to 1N ammoniumhydroxide (5 l, 5 moles). After the last addition, stirring was continued for still an hour. Some insoluble material was filtered off and the filtrate was carefully acidified with 6N sulphuric acid (835 ml) whilst cooling by the addition of crushed ice. After 1 hour the precipitate was collected, digested with water (2.5 l), filtered off and dried, yielding 180-270 g of a product containing 69-81% of the desired barbituric acid (by titration of the CH2), the remaining 19-31% consisting mainly of 1-cyclohexyl-2-acetyl-3-(2-sulphamoylphenyl)barbituric acid, as determined by TLC and NMR.
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19][CH3:20])=[C:17]2[C:12]([C:13](=[O:31])[C:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[C:15]([CH:21]([CH3:23])[CH3:22])[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>O1CCCC1.C(O)C.Cl.[Pd].[C]>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:14]2[C:13](=[O:31])[C:12]3[C:17](=[C:18]([O:19][CH3:20])[C:9]([OH:8])=[CH:10][CH:11]=3)[O:16][C:15]=2[CH:21]([CH3:23])[CH3:22])=[CH:29][CH:28]=1
Reactant: COc1c(OCc2ccccc2)ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: COc1c(O)ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 7-benzyloxy-3-(4-chlorophenyl)-2-isopropyl-8-methoxy-chromen-4-one (2.68 g, 6.16 mmol) and Pd/carbon (20%, 268 mg) in tetrahydrofuran (30 ml), absolute ethanol (30 ml) and 5M HCl solution (15 ml) is stirred under a balloon of H2 at room temperature for 3 h. The reaction mixture is filtered through a pad of Celite filter aid, which is itself washed with tetrahydrofuran. The solvent is removed under reduced pressure to afford the desired product, which is used without further purification.