Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][C:15]1[C:16]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[C:15]([CH3:14])=[CH:20][C:19]([CH3:21])=[CH:18][N:17]=3)[CH2:23][CH2:24]2)=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3[N+](=O)[O-])CC2)c(C)c1
Yield: 90.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 4-bromo-2-nitrobenzoic acid (2.3 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.91 g) described in Preparation Example 47, the title compound (3.54 g) was obtained.
Reaction SMILES: [ClH:1].Cl.S1C2C=CC([CH2:12][NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C@H:21]4[N:31]5[C:32]6[N:23]([C:24](=[O:34])[CH:25]=[CH:26][C:27]=6[CH:28]=[CH:29][C:30]5=[O:33])[CH2:22]4)[CH2:16][CH2:15]3)=CC=2N=N1.C(N(CC)CC)C.[O:42]1[C:46]2[CH:47]=[CH:48][C:49](C=O)=[CH:50][C:45]=2[CH2:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[O:42]1[C:46]2[CH:47]=[CH:48][C:49]([CH2:12][NH:13][CH:14]3[CH2:15][CH2:16][N:17]([CH2:20][C@H:21]4[N:31]5[C:32]6[N:23]([C:24](=[O:34])[CH:25]=[CH:26][C:27]=6[CH:28]=[CH:29][C:30]5=[O:33])[CH2:22]4)[CH2:18][CH2:19]3)=[CH:50][C:45]=2[CH2:44][CH2:43]1
Reactant: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2ccc3snnc3c2)CC1
Reactant: O=Cc1ccc2c(c1)CCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2ccc3c(c2)CCO3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
A suspension of (1R)-1-({4-[(1,2,3-benzothiadiazol-5-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (for a preparation see Example 5A(j)) (60 mg, 0.161 mmol) in chloroform (2 ml) and methanol (0.100 ml) at rt under nitrogen was treated with triethylamine (0.067 ml, 0.482 mmol) and stirred at rt for 15 min. The solution was then treated with 2,3-dihydro-1-benzofuran-5-carbaldehyde (commercially available) (0.020 ml, 0.161 mmol) and stirred for a further 30 min. The solution was then treated with sodium triacetoxyborohydride (102 mg, 0.482 mmol) and stirred at rt for 45 min. This was then treated with saturated aqueous NaHCO3 (10 ml) and extracted with 20% methanol/DCM (3×25 ml). The combined organic fractions were dried (NaSO4), filtered, evaporated and chromatographed (5-25% methanol/DCM) to give the free base of the title compound (24 mg, 34.5%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][P:15]([OH:18])(=[O:17])[OH:16])[C:9](=[O:19])[C:8](=[O:20])[NH:7]2)([O-])=O.C([O-])=O.[NH4+].O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][P:15]([OH:18])(=[O:16])[OH:17])[C:9](=[O:19])[C:8](=[O:20])[NH:7]2
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2n(CP(=O)(O)O)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc2c(c1)[nH]c(=O)c(=O)n2CP(=O)(O)O
Yield: 74 %

Procedure:
300 mg of 1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)methanephosphonic acid is dissolved in 60 mg of methanol and combined under nitrogen in succession with 50 mg of Pd/C (10%), 300 mg of ammonium formate, and 18 ml of water, and heated for one hour to 80° C. After cooling, the mixture is filtered off from the catalyst, the filtrate is concentrated by evaporation, and the residue is freeze-dried, thus obtaining 200 mg of 1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)methanephosphonic acid in the form of a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][CH:17]1[C:48](=[O:49])[N:19]2[CH:20]([C:32]([O:34][CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:21]([CH2:24][O:25]C(=O)CC(O)C)=[CH:22][S:23][C@H:18]12)=[O:15].S1[C@@H]2CC(=O)N2C=CC1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][CH:17]1[C:48](=[O:49])[N:19]2[CH:20]([C:32]([O:34][CH:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:33])[C:21]([CH2:24][OH:25])=[CH:22][S:23][C@H:18]12)=[O:15]
Reactant: CC(O)CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C1C[C@H]2SCC=CN12
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)=CS[C@H]12
Temperature: 25 °C

Procedure:
To 100 ml. of a solution of trifluoroacetic acid in methylene chloride (0.297 ml. trifluoroacetic acid in 125 ml. methylene chloride) at 0° C. was added 1.048 g. of a mixture of benzhydryl 7-(2-thienylacetamido)-3-(3-hydroxybutanoyloxymethyl)-2-cephem-4-carboxylate and the corresponding 3-cephem compound. After 6 hours a saturated aqueous sodium bicarbonate solution was added, and the mixture was allowed to warm to room temperature. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous MgSO4, and evaporated in vacuo to dryness. The foam thereby obtained was dissolved in methylene chloride; 59 mg. of 7-(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid lactone (the product derived from the 3-cephem starting material) crystallized and was filtered. The filtrate was concentrated in vacuo and cooled. Another 209 mg. of lactone, mixed with some of the title product, was obtained. Evaporation in vacuo to dryness of the resulting solution provided 680 mg. of the title product: nmr (acetone D-6 ) δ3.85 (s, 2, side chain CH2), 4.17 (s, 2, --CH2OH), 5.25 (d, 1, J = 4.5 Hz, C6 --H), 5.54 (dd, 1, J = 4.5 and 8.0 Hz, C7 --H), 6.40 (bs, 1, C2 --H), 6.95 (s, 1, ester CH), 7.32 (m, 13, thienyl + ArH), and 8.04 (d, 1, J = 8.0 Hz, side chain NH).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:25](O)=O>>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(Cl)cc(Cl)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3,5-dichlorobenzoic acid: MS (APCI) m/z 439 (M+1).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:34])[C@H:24]([CH:26](C(C)(C)C)[C:27]([OH:29])=[O:28])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]([O:29][C:27](=[O:28])[CH2:26][C@@H:24]([C:23]([OH:22])=[O:34])[NH:25][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:19])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH3:19])([CH3:7])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)C(C(=O)O)C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
N-(Toluene4-sulfonyl)-L-proline hydrate was coupled to β-tert-butyl L-aspartic acid methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared, via hydrolysis of the methyl ester using LiOH in THF/water, as a solid, mp=153-155° C.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29](F)(F)F)=[CH:4][CH:3]=1.IC1SC2CCCCCC=2N=1>>[NH:25]1[CH2:26][CH2:27][CH:22]([N:20]2[CH:21]=[C:17]([C:15]3[CH:16]=[C:11]([C:8]4[S:9][C:10]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:29][C:6]=5[N:7]=4)[C:12]([NH2:28])=[N:13][CH:14]=3)[CH:18]=[N:19]2)[CH2:23][CH2:24]1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Agent: Ic1nc2c(s1)CCCCC2
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(s1)CCCCC2

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-iodo-5,6,7,8-tetrahydro-4H-cycloheptathiazole and conducting the Suzuki coupling at 55° C. for 3 h, the title compound was obtained as a yellow solid. MS (ES+): m/z=395.19 [MH+]. HPLC: tR=2.21 min (ZQ3, polar—5 min).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[NH:6][C:7]1[S:8][C:9]([CH3:14])=[CH:10][C:11]=1[C:12]#[N:13])([O-])=O.[ClH:19]>C(O)C>[ClH:19].[NH2:13][C:12]1[C:11]2[CH:10]=[C:9]([CH3:14])[S:8][C:7]=2[NH:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:1]=1
Reactant: Cc1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Agent: Cl
Solvent: CCO
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N

Procedure:
To a stirred slurry of 2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile (3 g, 0.011 mol) in ethanol (35 mL) at 50° C. was added, over 10 minutes, a solution of anhydrous stannous chloride (6.95 g, 0.037 mol) in hydrochloric acid (26 mL, 5M). The mixture was stirred under reflux for 1 hour, concentrated under reduced pressure and allowed to crystallize over night at 5° C. The salt was filtered, washed with a small amount of water, dried (4.3 g) m.p. >250° C., and used without further purification in the next stage.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([CH:16]1[CH:20]([C@@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:19][N:18](CC2C=CC=CC=2)[CH2:17]1)=[O:15].O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:12][O:13][C:14]([CH:16]1[CH:20]([C@@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:19][N:18]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17]1)=[O:15]
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1[C@@H](C)CO[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@@H](C)CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Benzyloxycarbonyl chloride (10.2 mL, 71.5 mmol) was added to a solution of 1-benzyl-4-[(R)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]pyrrolidine-3-carboxylic acid methyl ester (14.0 g, 35.8 mmol) in dichloromethane (200 mL), and the mixture was stirred for one hour. Saturated sodium bicarbonate water was added to the reaction mixture. The organic layer was separated, dried over magnesium sulfate, and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 13.9 g (89%) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[CH2:29][OH:30]>O>[CH3:22][CH:21]([N:20]1[C:16]([C:10]2[N:11]=[C:12]3[N:8]([CH:9]=2)[CH2:7][CH2:6][O:5][C:4]2[C:13]3=[CH:14][N:15]=[C:2]([N:24]3[CH2:28][CH2:27][CH2:26][CH:25]3[CH2:29][OH:30])[CH:3]=2)=[N:17][CH:18]=[N:19]1)[CH3:23]
Reactant: OCC1CCCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCCC3CO)cc1OCC2
Temperature: 160 °C
Reaction time: 4 h
Yield: 57.8 %

Procedure:
A mixture of 12-chloro-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene from Example 135 (500 mg, 1.51 mmol) and pyrrolidin-2-yl-methanol (1.00 g, 9.89 mmol) was stirred at 160° C. for 4 hr. The resulting mixture was poured into water and extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and evaporated to give the crude product, which was purified by reverse phase combiflash eluting with 0-50% gradient of CH3CN in 0.5% NH4HCO3 to give (1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}pyrrolidin-2-yl)methanol as white solid (345 mg, 58% yield). LCMS (ESI) m/z: 396.2 [M+H+].
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]([C:9]2[N:10]([CH2:25][C:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[S:28][CH:27]=3)[N:11]=[C:12]3[C:17]=2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]3[CH2:21][CH:22]([CH3:24])[CH3:23])[N:6]([CH3:8])[CH:7]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(N(CC)CC)C>[S:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]([CH2:25][N:10]2[C:9]([C:5]3[N:6]([CH3:8])[CH:7]=[C:3]([NH:2][C:35](=[O:37])[CH3:36])[N:4]=3)=[C:17]3[C:12]([N:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:14](=[O:20])[N:15]([CH3:19])[C:16]3=[O:18])=[N:11]2)=[CH:27]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nc(N)cn3C)n(Cc3csc4ccccc34)nc21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cn(C)c(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2csc3ccccc23)n1

Procedure:
This compound was synthesized by the reaction of 3-(4-amino-1-methyl-1H-imidazol-2-yl)-2-(1-benzothien-3-ylmethyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione hydrochloride and acetyl chloride using triethylamine as a base. Mass: 506.09 (M+H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[Cl:5][C:6]1[N:7]=[N:8][C:9](Cl)=[CH:10][CH:11]=1.C(N(CC)C(C)C)(C)C>C(O)CC>[N:1]1([C:9]2[N:8]=[N:7][C:6]([Cl:5])=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ccc(Cl)nn1
Reactant: C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: Clc1ccc(N2CCC2)nn1
Temperature: 25 °C
Reaction time: 216 h
Yield: 84.7 %

Procedure:
Azetidine (250 mg) was added to a stirred solution of 3,6-dichloropyridazine (650 mg) and N,N-diisopropyl-ethylamine (0.9 mL) in n-propanol (10 mL). The mixture was stirred at room temperature for 9 days and then concentrated. The solid residue was partitioned between ethyl acetate (100 mL) and water (10 mL). The organic layer was separated and washed with brine (10 mL), dried (Na2SO4), and concentrated to leave a white solid (627 mg). Chromatography on a 12-g silica gel cartridge (eluted with a 0-100% ethyl acetate in hexanes gradient) afforded the title compound as a white solid. Yield: 441 mg (59% of theory); 1H NMR (CDCl3) δ 2.47 (m, 2H), 4.13 (m, 4H), 6.48 (d, 1H), 7.16 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2S[CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O[O:22][S:23]([O-:25])=O.[K+].OS([O-])(=O)=O.[K+]>CO>[Br:1][C:2]1[S:6][C:5]([CH:7]2[S:23](=[O:25])(=[O:22])[CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCSC(c2ccc(Br)s2)CC1
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)s2)S(=O)(=O)CC1
Reaction time: 4 h

Procedure:
To a solution of 7-(5-bromo-2-thienyl)-4-tert-butoxycarbonylperhydro-1,4-thiazepine (73.8 g) in methanol (500 ml) was added an aqueous solution (500 ml) of OXONE (2KHSO5.KHSO4.K2SO4) (156 g) under ice-cooling. After being stirred for 4 hours, the reaction mixture was concentrated in vacuo to remove methanol. The residue was extracted with ethyl acetate (1000 ml) and the extract was washed successively with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was washed with hexane to afford 7-(5-bromo-2-thienyl)-4-tert-butoxycarbonylperhydro-1,4-thiazepine 1,1-dioxide (64.6 g) as a solid.
Reaction SMILES: [CH2:1]([C:8]1(Br)[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:22])[C:16]=3[Cl:21])[NH:11][C:10]=2[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Br-]>CN(C=O)C.O>[CH2:1]([C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:22])[C:16]=3[Cl:21])[NH:11][C:10]=2[C:9]=1[OH:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2[nH]c3ccc(Cl)c(Cl)c3c2CCC1(Br)Cc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1c(Cc2ccccc2)ccc2c1[nH]c1ccc(Cl)c(Cl)c12
Temperature: 90 °C
Yield: 55.1 %

Procedure:
2-Benzyl-2-bromo-5,6-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.48 g, 1.14 mmol) was dissolved in DMF (4 mL) and LiBr (0.1 g, 1.25 mmol) followed by Li2CO3 (0.09 g, 1.25 mmol) were added. The reaction mixture was heated to 90° C. for 1 h, then cooled to room temperature, diluted with water and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography [EtOAc-hexane (3:17) as eluant] to provide the title compound as a light green solid (0.215 g, 56%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.31 (s, 1H), 9.22 (s, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.52 (s, 2H), 7.26-7.23 (m, 4H), 7.18-7.20 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 4.14 (s, 2H).
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH3:25])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2].[C:26]([O-])(=O)[CH3:27].[Na+].C(O)(=O)C.[BH4-].[Na+]>>[CH2:1]([N:3]([CH2:26][CH3:27])[CH:4]([CH3:25])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2]
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3c(OC)c(OC)ccc23)C1
Reactant: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN(CC)C(C)CN1CCc2c(c(=O)oc3c(OC)c(OC)ccc23)C1
Yield: 21.2 %

Procedure:
Prepared by the method described in Example 73 from 3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (10.0 g, 0.029 moles), sodium acetate (4.7 g, 0.058 moles), acetic acid (43.2 g, 0.72 moles), and sodium borohydride (5.9 g, 0.16 moles). Several recrystallizations from ethyl acetate/hexane yielded the product as the free base (2.3 g), mp 99°-100° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:16]=[CH:17][C:10]=23)O1.Br[C:39]1[CH:40]=[C:41]([C:45]([CH3:50])([CH2:48][CH3:49])[C:46]#[N:47])[CH:42]=[CH:43][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:50][C:45]([C:41]1[CH:40]=[CH:39][CH:44]=[C:43]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:16]=[CH:17][C:10]=23)[CH:42]=1)([CH2:48][CH3:49])[C:46]#[N:47]
Reactant: CC1(C)OB(c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)OC1(C)C
Reactant: CCC(C)(C#N)c1cccc(Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(C)(C#N)c1cccc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine (307 mg, 0.630 mmol), 2-(3-bromophenyl)-2-methylbutanenitrile (150 mg, 0.630 mmol) and 2 M aqueous solution of sodium carbonate (0.945 ml, 1.89 mmol) in dioxane (4 ml) was degassed by vacuum/nitrogen cycles (×5). Bis(tri-tert-butylphosphine)palladium(0) (16.10 mg, 0.032 mmol) was added and the resultant mixture was degassed by vacuum/nitrogen cycles (×5) and stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium carbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a sticky white solid (0.240 mg, 80% purity, 59% yield).
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=3[F:19])[C:6]=2[C:5]([F:20])=[C:4]([F:21])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1>C1COCC1>[CH:32]1([S:35]([N:9]2[C:10]3[C:2]([F:1])=[CH:3][C:4]([F:21])=[C:5]([F:20])[C:6]=3[N:7]([C:12]3[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=3[F:19])[C:8]2=[O:11])(=[O:37])=[O:36])[CH2:34][CH2:33]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2c(F)cc(F)c(F)c2n1-c1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1n(-c2ccc(I)cc2F)c2c(F)c(F)cc(F)c2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 4,6,7-trifluoro-1-(2-fluoro-4-iodo-phenyl)-1,3,-dihydrobenzimidazol-2-one (0.2 gm, 0.41 mmol) in dry THF (4 ml) under nitrogen was cooled to −78° C. and a solution of 1.0 M LiHMDS (0.41 ml, 0.41 mmol) was added slowly, (2 ml) followed by addition of cyclopropanesulfonyl chloride (0.050 ml, 0.49 mmol). This reaction mixture was kept stirring at room temperature for 16 hours, concentrated to dryness and was taken into EtOAc. The EtOAc was washed with water, dried over sodium sulfate and concentrated to dryness. The residue obtained 1-cyclopropanesulfonyl-4,5,7-trifluoro-3-(2-fluoro-4-iodo-phenyl)-1,3-dihydro-benzimidazol-2-one 5 was taken into dioxane (2 ml) and to this 1.0 N NaOH (0.5 ml) was added and kept stirring at room 50° C. for 16 hours. TLC indicated incomplete reaction, the product was purified by HPLC to provide off-white solid (4.4 mg) M+H+: 484.7, M−H+: 486.7. 1H NMR (CDCl3, 300 MHZ): 0.9-1.1-(m, 2H); 1.1-1.2 (m, 2H); 2.45-2.55 (m, 1H); 6.05 (s, 1H); 6.44-6.54 (m, 1H); 7.1 (s, 1H); 7.4-7.7 (d, 1H); 7.38-7.44 (dd, 1H); m/z=485 [M−1]−.
Reaction SMILES: [Cl:1][CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.CO.C1C(=O)N(Br)C(=[O:16])C1>O>[Cl:1][CH2:2][S:3]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(SCCl)cc1
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)CCl)cc1
Yield: 89.5 %

Procedure:
(Choromethyl)(p-tolyl)sulfane (10 g, 57.91 mmol) was added to a mixture of methanol (50 mL) and water (10 mL). The resulting mixture was cooled to a temperature between 0° C. and 5° C. NBS (12.37 g, 1.2 eq) was added in small portions, maintaining the same temperature range. The reaction mixture was stirred within the same temperature range until the reaction was complete. Thereafter, the reaction mixture was quenched by the addition of Na2SO3 (10%, 30 mL). The pH of the reaction mixture was adjusted to a value between 7 and 8, with saturated NaHCO3 solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. and then extracted with dichloromethane (40 mL, 30 mL). The combined organic layer was washed with water (2×60 ml) and concentrated to ⅓ of the volume. Heptane (10 mL) was added and then removed by distillation. The crude product was purified by flash chromatography (Ethyl Acetate/Hexane 30:70) to give 9.78 g (89.51%) of the desired product as a white solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][NH:7][C:8]1[N:13]=[C:12]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH2:27][CH3:28])[NH:16][C:17](=[O:18])[C:11]2=[CH:10][N:9]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([CH2:6][NH:7][C:8]1[N:13]=[C:12]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH2:27][CH3:28])[NH:16][C:17](=[O:18])[C:11]2=[CH:10][N:9]=1)([OH:5])=[O:3]
Reactant: CCCOc1ccccc1-c1nc2nc(NCC(=O)OCC)ncc2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1ccccc1-c1nc2nc(NCC(=O)O)ncc2c(=O)[nH]1
Yield: 81.9 %

Procedure:
In a similar manner to Example 59 reaction of 7-(ethoxycarbonylmethylamino)4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.54 g) and 1 Normal sodium hydroxide (5 ml) yielded the title compound 0.41 g, m.p. 252-253.5° C. (dec.) (recrystallized from ethanol:water).