Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:18][C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][C:24]([Cl:30])=[CH:25][CH:26]=2)[N:21]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]=1[C:37]([O:39][CH3:40])=[O:38]>CN1C(=O)CCC1>[CH3:40][O:39][C:37]([C:20]1[N:21]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:22]2[C:27]([C:28](=[O:29])[C:19]=1[CH2:18][N:2]([C:3](=[O:14])[C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1)[CH3:1])=[CH:26][CH:25]=[C:24]([Cl:30])[CH:23]=2)=[O:38]
Reactant: CNC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: COC(=O)c1c(CBr)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1c(CN(C)C(=O)c2ccc(S(C)(=O)=O)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reaction time: 0.08 h
Yield: 20.8 %

Procedure:
To a stirred solution of N-methyl-4-(methylsulfonyl)benzamide (25.2 mg, 0.118 mmol) in NMP was added sodium hydride (60% suspension) (3.54 mg, 0.148 mmol). After 5 min., methyl 3-(bromomethyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylate (40 mg, 0.098 mmol) was added and the mixture was allowed to stir for 3 hr. at room temp. The mixture was then quenched with water and acidified with 1N aqueous HCl. The mixture was then extracted with CH2Cl2. The extracts were dried (Na2SO4), filtered and concentrated in vacuo. Preparative reverse-phase HPLC afforded 7-chloro-3-{[(4-methanesulfonyl-benzoyl)-methyl-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (11 mg, 20%) as an off-white foam. MS calcd. for C27H23ClN2O6S [(M+H)+] 539, obsd. 539.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([NH:4][C:3]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1cccc(C)c1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2c(C)cccc2C)cc1
Yield: 136.2 %

Procedure:
A solution of 23.4 g (0.12 mole) of 2,6-dimethylaniline and 40.5 g (0.19 mole) of p-toluenesulfonyl chloride in 75 ml of pyridine was heated at reflux for three hours. The mixture was cooled and poured into vigorously stirred 2N hydrochloric acid. The crude product was recrystallized from ethanol to give 45 g of the title compound. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: Cl[Si:2](Cl)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:16]([C:32]1[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=[C:34]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:33]=1[OH:46])[C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=1[OH:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:38]([C:36]1[CH:35]=[C:34]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:33]2[O:46][Si:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:31][C:18]3[C:19]([C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:22][C:17]=3[S:16][C:32]=2[CH:37]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)c1cc(Sc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[Si](c1ccccc1)(c1ccccc1)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)S2
Temperature: 92 °C
Yield: 43.3 %

Procedure:
A solution of 12.66 grams of dichlorodiphenylsilane in 50 ml of toluene at 5°-10° C. is added dropwise to a solution of 22.14 grams of 2,2'-thiobis(4,6-di-tert-butylphenol) and 10.12 grams of triethylamine in 100 ml of toluene. The reaction mixture is heated at 92° C. until the reaction is complete as evidenced by the disappearance of the phenolic absorption in the IR spectrum. The triethylamine hydrochloride is removed by filtration and the solvent is removed in vacuo. The residue is recrystallized from 2-butanone to give 13.49 grams (43%) of a white solid: mp 202°-205° C.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:25][C:23](=[O:24])[C@H:22]([CH3:26])[C@@H:21]([O:27][C@@H:28]2[O:33][C@@H:32]([CH3:34])[C@H:31]([OH:35])[C@@:30]([O:37][CH3:38])([CH3:36])[CH2:29]2)[C@H:20]([CH3:39])[C@@H:19]([O:40][C@@H:41]2[O:46][C@H:45]([CH3:47])[CH2:44][C@H:43]([N:48]([CH3:50])[CH3:49])[C@H:42]2[OH:51])[C@@:18]([OH:53])([CH3:52])[CH2:17][C@@H:16]([CH3:54])/[C:7](=[N:8]\[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])/[C@H:6]([CH3:55])[C@@H:5]([OH:56])[C@@:4]1([OH:58])[CH3:57]>C(Cl)Cl>[CH3:1][CH2:2][C@H:3]1[O:25][C:23](=[O:24])[C@H:22]([CH3:26])[C@@H:21]([O:27][C@@H:28]2[O:33][C@@H:32]([CH3:34])[C@H:31]([OH:35])[C@@:30]([O:37][CH3:38])([CH3:36])[CH2:29]2)[C@H:20]([CH3:39])[C@@H:19]([O:40][C@@H:41]2[O:46][C@H:45]([CH3:47])[CH2:44][C@H:43]([N:48]([CH3:49])[CH3:50])[C@H:42]2[O:51][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[C@@:18]([OH:53])([CH3:52])[CH2:17][C@@H:16]([CH3:54])/[C:7](=[N:8]/[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])/[C@H:6]([CH3:55])[C@@H:5]([OH:56])[C@@:4]1([OH:58])[CH3:57]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)/C(=N\OCOCCOC)[C@H](C)[C@@H](O)[C@]1(C)O
Solvent: ClCCl
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2OCOCCOC)[C@](C)(O)C[C@@H](C)/C(=N/OCOCCOC)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 120 h

Procedure:
Roxithromycin (30 grams) was dissolved in a solution of Eudragit RS100 (70 grams) in methylene chloride (560 grams). The solution was pumped through an atomising nozzle into a spray drier with an inlet air temperature of 55° C. The powder was collected and suspended in a 0.05M glycine buffer at pH 10 containing 1% polyvinylpyrollidone. The taste due to the roxithromycin was not detectable 5 days after preparation.
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[N:6][CH:5]=[C:4]([NH2:9])[N:3]=1.[NH3:10]>C(O)C>[NH2:10][C:2]1[C:7]([Br:8])=[N:6][CH:5]=[C:4]([NH2:9])[N:3]=1
Reactant: Nc1cnc(Br)c(Cl)n1
Reactant: N
Solvent: CCO
Product: Nc1cnc(Br)c(N)n1
Temperature: 160 °C
Reaction time: 16 h

Procedure:
A suspension of 2-chloro-3-bromo-6-aminopyrazine (15 g, 0.072 mole) in absolute ethanol (150 ml) and 0.880 ammonia (375 ml) was stirred and heated in an autoclave at 160° C. and 20 atm. for 16 hrs. The cooled mixture was evaporated in vacuo and extracted with hot methanol (3×100 ml). The combined methanol extracts were evaporated in vacuo. The residue was dissolved in hot chloroform, dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was triturated with 40-60° C. petroleum ether, filtered, and dried in vacuo. Yield 5.51 g (40%), M.p. 176-178° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12].[CH3:15][O:16][C:17]1[CH:22]=[C:21](B(O)O)[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:2]([C:21]2[CH:20]=[CH:19][N:18]=[C:17]([O:16][CH3:15])[CH:22]=2)[CH:7]=1
Reactant: C[Si](C)(C)C#Cc1ccc(Cl)cc1Br
Reactant: COc1cc(B(O)O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(-c2cc(Cl)ccc2C#C[Si](C)(C)C)ccn1

Procedure:
A solution of 333 mg (1.16 mmol) of [(2-bromo-4-chlorophenyl)ethynyl](trimethyl)silane, 195 mg (1.28 mmol, 1.1 eq.) of (2-methoxypyridin-4-yl)boronic acid, 401 mg (2.9 mmol, 2.5 eq.) of potassium carbonate and 14 mg (0.02 mmol, 0.015 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/monodichloromethane adduct in 18 ml of dioxane was irradiated in a microwave at 130° C. for 15 min. The reaction mixture was then filtered through Celite and the residue was washed with dioxane. The combined filtrates were concentrated under reduced pressure. After addition of water/ethyl acetate and phase separation, the organic phase was concentrated under reduced pressure. Yield: 550 mg (purity 41%, 62% of theory)
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[O:1][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5]
Reactant: COc1cccc(C=O)c1O
Reactant: CCOC(=O)C(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1c(C=O)cccc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 104.2 %

Procedure:
A mixture of 2-hydroxy-3-methoxybenzaldehyde (3.04 g), ethyl 2-bromopropionate (5.85 g), and potassium carbonate (4.14 g) in dimethylsulfoxide (20 ml) was stirred at 70° C. for 5 hours. The mixture was diluted with water, neutralized with 1N hydrochloric acid, and was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated. The crude product (0.93 g) was purified on a silica gel column (60 g) eluting with a mixed solvent of n-hexane and toluene (from 6:1 to 5:1) to give ethyl 2-(2-formyl-6-methoxyphenoxy)-propionate (5.25 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH:7]=O.Cl.[NH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]1[C:24]2[CH:25]=[CH:26][N:27]=[C:28]([Cl:33])[C:29]=2[CH:30]=[CH:31][CH:32]=1)(=[O:22])=[O:21].CCN(CC)CC.[BH4-].[Na+]>CO>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH:16][CH2:17][CH2:18][NH:19][S:20]([C:23]1[C:24]2[CH:25]=[CH:26][N:27]=[C:28]([Cl:33])[C:29]=2[CH:30]=[CH:31][CH:32]=1)(=[O:21])=[O:22]
Reactant: O=CCOc1ccccc1C(F)(F)F
Reactant: NCCNS(=O)(=O)c1cccc2c(Cl)nccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=S(=O)(NCCNCCOc1ccccc1C(F)(F)F)c1cccc2c(Cl)nccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A 4.2 mL of the (2-trifluoromethyl-phenoxy)-acetaldehyde stock solution (˜0.69 mmol) is added to a stirred mixture of 1-chloro-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide hydrochloride (200 mg, 0.621 mmol), 4 Å molecular sieve (400 mg) and NEt3 (0.19 mL, 1.4 mmol) in anhydrous CH3OH (5 mL) at ambient temperature under nitrogen. The resultant mixture is stirred for 16 hours. The mixture is cooled to 0° C. before it is treated with powdered sodium borohydride (53 mg, 1.4 mmol). The mixture is stirred at 0° C. for 1 hour and at ambient temperature for another 1 hour. After filtration and subsequent concentration in vacuo, the crude product is chromatographed on silica (gradient 0-5% CH3OH in CH2Cl2) to give 92 mg (0.19 mmol, 31% yield) of 1-chloro-isoquinoline -5-sulfonic acid {2-[2-(2-trifluoromethyl-phenoxy)-ethylamino]-ethyl}-amide. ESIMS: m/z 474 [(M+H)+, 35Cl], 476 [(M+H)+, 37Cl].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>CC(N(C)C)=O>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[NH2:11])[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1cccc(O)c1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc(Oc2cccc(N)c2)ccn1

Procedure:
Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][C:13]([CH:32]=[CH2:33])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][C:13]([CH:32]=[CH2:33])=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: C=Cc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3[nH]cnc23)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 111 %

Procedure:
N-(6-Methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-vinylpyridin-2-amine (76.3 mg, 0.172 mmol) was dissolved in DCM (2.9 mL) and trifluoroacetic acid (Aldrich, St. Louis, Mo., hplc grade, 0.60 mL, 7.8 mmol) was added via syringe. The reaction was stirred at room temperature for 35 minutes, concentrated, treated with MeOH, and filtered. The solid was washed with Et2O, but was not sufficiently (>95% by HPLC) pure. So, the solid and filtrate were combined, concentrated, treated with 2N ammonia in MeOH, and concentrated again. The material was treated with Et2O, but this did not precipitate product. So, it was concentrated, treated with water, and filtered. The solid was washed with water, but was still not 95% pure. So, the solid was collected and purified on HPLC (10% to 100% MeCN/water over 30 minutes using a total flow rate of 100 mL/min) to afford N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-vinylpyridin-2-amine (68.6 mg). MS (ESI pos. ion) m/z 360 (M+H)+. 1H NMR (d6-DMSO) δ 12.70 (s, 1H), 9.98 (s, 1H), 8.65 (s, 1H), 8.55 (d, J=2.54 Hz, 1H), 8.40 (d, J=2.35 Hz, 1H), 8.19 (dd, J=8.8 Hz, 2.74 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.79 (dd, J=17.5 Hz, 10.9 Hz, 1H), 5.78 (d, J=16.4 Hz, 1H), 5.26 (d, J=11.0 Hz, 1H), 3.85 (s, 3H), 2.86 (s, 3H).
Reaction SMILES: C[C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].[H-].[Na+].ClC[CH:18]1C[CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19]1>CN(C)C=O>[C:24]1([CH2:23][N:20]2[CH2:19][CH2:18][CH:3]([CH2:2][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[NH:6][C:5]3=[O:13])[CH2:21]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: ClCC1CCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1CC1CCN(Cc2ccccc2)C1
Temperature: 110 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a stirred mixture of 43.5 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one and 270 parts of N,N-dimethylformamide are added portionwise 10 parts of sodium hydride dispersion 60%. After stirring for 1 hour at about 40°-50° C., there are added 53 parts of 3-(chloromethyl)-1-(phenylmethyl)pyrrolidine and the whole is stirred and heated overnight at about 110° C. The reaction mixture is cooled and poured onto water. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is taken up in a diluted hydrochloric acid solution and the whole is stirred for 1 hour at room temperature. After cooling, the mixture is alkalized and the product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is triturated in 2,2'-oxybispropane with activated charcoal. The latter is filtered off and the filtrate is allowed to crystallize. The product is filtered off and dried, yielding 40 parts (53%) of 1,3-dihydro-1-[1-(phenylmethyl)-3-pyrrolidinylmethyl]-2H-benzimidazol-2-one.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[SH:12][CH2:13][C:14]([OH:16])=[O:15]>[OH-].[Na+].C1COCC1.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CSCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4-Nitrobenzyl chloride (2.5 g, 15 mmol) was added to a solution of mercaptoacetic acid (80% in H2O, 1 mL,~12 mmol) in aqueous sodium hydroxide (2.75N, 10 mL) and THF (10 mL) with stirring at 50° C. After 1 hour, the reaction was cooled to ambient temperature, diluted with water (30 mL) and extracted with Et2O to remove excess halide. The aqueous layer was distributed between EtOAc and 5% citric acid and the organic extract then washed with H2O, dried (MgSO4) and evaporated to give the title compound as a pale yellow solid, m.p. 101-104° C. [lit. m.p. 114° C⟧ 1H NMR (CDCl3); δ3.10 (s, 2H), 3.94 (s, 2H), 5.37 (d, 2H, J =8.7 Hz), 8.21 (d, 2H, J=8.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)[C:5]([Cl:16])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc(Cl)cc(C(=O)O)c1
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-Chloro-5-cyanobenzoic acid (0.82 g, 4.97 mmol) was treated with a solution of oxalyl chloride (10 mL of 2.5 M in dichloromethane, 25 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuo to afford 3-chloro-5-cyanobenzoyl chloride.
Reaction SMILES: C[O:2][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=O.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:2])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 16 h
Yield: 38 %

Procedure:
5 g of adenosine-5'-carboxylic acid methyl ester are heated together with 100 ml of tert.-butylamine on a streambath until a clear solution is obtained and thereafter the reaction mixture is left to stand for 16 hours at ambient temperature. Excess tert.-butylamine is then distilled off and the residue is mixed with methanol, again evaporated to dryness and the solid residue, after slurrying in cold methanol is filtered off with suction. After recrystallizing twice from a little methanol, there are obtained 2.15 g (38% of theory) of adenosine-5'-carboxylic acid N-tert.-butylamide, which melts, with decomposition, at 279°-280° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]3[C:24]=2[N:23]([CH3:25])[C:22]([CH3:26])=[C:21]3[CH3:27])[C:7]1=[O:29].O.[OH-].[Li+]>C1COCC1.O>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]([CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:7]2=[O:29])=[C:24]2[C:20]=1[C:21]([CH3:27])=[C:22]([CH3:26])[N:23]2[CH3:25]
Reactant: COC(=O)CCn1c(=O)n(Cc2ccc(Cl)c3c(C)c(C)n(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C)n(C)c2c(Cn3c(=O)n(CCC(=O)O)c4ccccc43)ccc(Cl)c12
Temperature: 25 °C
Yield: 13.5 %

Procedure:
To a stirred solution of 3-[3-(4-chloro-1,2,3-trimethyl-1H-indol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid methyl ester (40 mg, 0.09 mmol) in THF (3 ml) and water (1 ml) was added lithium hydroxide monohydrate (10 mg, 0.24 mmol). The resulting mixture was stirred at ambient temperature until all of the starting material was consumed. After this time the reaction was concentrated to low volume and diluted with water (10 ml) and acetic acid (0.5 ml). The resulting heterogeneous mixture was stirred at ambient temperature for 18 h. The solid product was collected via filtration and suspended in acetonitrile. The product was collected once more via filtration and washed with minimal acetonitrile to give 5 mg (13%) of the desired product. LCMS (ESMS): m/z 412.88 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]3[N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]4([CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][S:18](=[O:21])(=[O:22])[CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCS(=O)(=O)CC2)c2ccc(N3CCOCC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)CCC2(CC1)CNc1cc(N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 6-(4-morpholinyl)-2′,3′,5′,6′-tetrahydrospiro-[indole-3,4′-thiopyran]-1(2H)-carboxylate 1′,1′-dioxide (60 mg, 0.142 mmol) in DCM (1 mL) was added TFA (438 μL, 5.68 mmol) and the reaction was stirred at rt for 1 h. After this time the reaction was evaporated in vacuo and dried on the vacuum pump overnight. The resulting residue was then partitioned between DCM (40 mL) and NaHCO3 (10 mL, sat. aqueous solution). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo to give 6-morpholin-4-yl-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran]1′,1′-dioxide. Mass Spectrum (ESI) m/e=323.2 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:12][NH:11][CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:38](O)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:31])[NH:32][C:33]1([C:38]([N:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)[CH2:14][CH:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:8]=3)[CH2:10]2)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Reactant: FC(F)(F)c1ccc(C2CNCC(c3nc(C4CC4)no3)C2)cc1
Product: CC(C)(C)OC(=O)NC1(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(C4CC4)no3)C2)CCCC1

Procedure:
100 mg (0.30 mmol) of the compound from Example 183A and 75 mg (0.33 mmol) of 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid were reacted according to the General Method 7. Yield: 127 mg (78% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].Br[CH2:14][C:15]#[N:16]>CN(C)C=O.C(OCC)(=O)C>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:14][C:15]#[N:16])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: N#CCBr
Reactant: Oc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
A 0° C. solution of 4-hydroxyindole (20 g, 150 mmol) in 500 ml of dimethylformamide is treated with NaH (60% dispersion in mineral oil; 6.6 g, 165 mmol). After 30 minutes, bromoacetonitrile (11.5 ml, 165 mmol) is added, and the resulting mixture is allowed to slowly warm to ambient temperature and stir for 3 days. The reaction mixture is diluted with ethyl acetate and washed 3 times with H2O. The organic layer is dried over Na2SO4 and concentrated in vacuo. The crude residue is purified by normal phase HPLC (SiO2; 5% step gradient of 0 to 20% ethyl acetate in hexanes) to give 25 g of (1H-indol-4-yloxy)acetonitrile (97%).