Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>C(O)(=O)C>[N+:16]([CH2:19][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:13][CH:12]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc(Oc2ccccc2)nc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(Oc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
To a solution of 6-phenoxy-pyridine-3-carbaldehyde (1.12 g, 5.62 mmol) described in Manufacturing Example 40-1-2 in acetic acid (10 mL) were added nitromethane (1.52 mL, 28.1 mmol) and ammonium acetate (866 mg, 11.2 mmol) under nitrogen atmosphere, which was stirred for 3 hours at 100° C. After being cooled to room temperature, the reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The resulting residue was dissolved in dimethyl sulfoxide (17 mL) and acetic acid (3 mL). Sodium borohydride (336 mg, 8.43 mmol) was added to this solution at room temperature while cooling appropriately, and stirred for 30 minutes at room temperature. The reaction solution was partitioned by addition of sodium hydrogencarbonate, water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (753 mg, 55%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[C:41]([C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1)#[N:42]>O1CCCC1.O>[C:41]([C:43]1[CH:44]=[C:45]([S:49]([N:7]2[C:8]([C:9]3[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=3)=[C:4]([F:3])[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6]2)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1)#[N:42]
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 91.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-cyanobenzenesulfonyl chloride (302 mg) under ice-cooling and the mixture was stirred for 17 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 446 mg, 91%).
Reaction SMILES: [CH2:1]([CH2:7]Cl)[CH2:2][O:3][C:4](Cl)=[O:5].[NH2:9][C:10]1[CH:11]=[C:12]([Cl:34])[C:13]([N:16]2[CH2:33][CH2:32][CH2:31][C@@:18]3([C:22](=[O:23])[N:21]([C@H:24]4[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[CH2:17]2)=[N:14][CH:15]=1.O[C@H]1CC[C@H](N2CC[C@]3(CCCNC3)C2=O)CC1.CC(C)([O-])C.[K+].C(O)(C(F)(F)F)=O>CN(C)C1C=CN=CC=1.CN(C=O)C.O1CCCC1.CO>[Cl:34][C:12]1[C:13]([N:16]2[CH2:33][CH2:32][CH2:31][C@@:18]3([C:22](=[O:23])[N:21]([C@H:24]4[CH2:25][CH2:26][C@H:27]([OH:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[CH2:17]2)=[N:14][CH:15]=[C:10]([N:9]2[CH2:7][CH2:1][CH2:2][O:3][C:4]2=[O:5])[CH:11]=1
Reactant: Nc1cnc(N2CCC[C@]3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)c(Cl)c1
Reactant: O=C(Cl)OCCCCl
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: O=C1N([C@H]2CC[C@H](O)CC2)CC[C@]12CCCNC2
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C1OCCCN1c1cnc(N2CCC[C@]3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)c(Cl)c1
Reaction time: 1 h

Procedure:
3-Chloropropyl chloridocarbonate (15.1 μL, 0.000125 mol) was added to a mixture of (5S)-7-(5-amino-3-chloropyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (37.89 mg, 0.0001000 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 105, step 1 starting from (5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one) and 4-dimethylaminopyridine (18.3 mg, 0.000150 mol) in DMF (1.00 mL). After stirring the mixture for 1 h, 1.0000 M of potassium tert-butoxide in tetrahydrofuran (0.375 mL) was added and the resultant mixture was stirred at rt for 2 h. The mixture was diluted with methanol (0.8 mL) and was adjusted to pH=2.0 with TFA. The resulting solution was purified by prep.-HPLC to give the desired product. LC-MS: 463.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCCCc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCCc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.56 g (5.14 mmol) of 3-[5-(imidazo[1,2-a]pyridin-5-yl)pentyl]thiazolidine-2,4-dione and 0.46 ml (5.14 mmol) of n-butyraldehyde in 50 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate→ethyl acetate/ethanol=10/1) to yield 1.37 g (74.6%, light yellow oily substance) of the desired product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[C:29]3[CH:30]=[CH:31][C:32](O)=[CH:33][C:28]=3[O:27][N:26]=2)[CH2:20]1>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:32]1[CH:31]=[CH:30][C:29]2[C:25]([N:21]3[CH2:20][C@H:19]([CH2:18][O:17][CH3:16])[O:23][C:22]3=[O:24])=[N:26][O:27][C:28]=2[CH:33]=1)(=[O:5])=[O:4]
Reactant: COC[C@H]1CN(c2noc3cc(O)ccc23)C(=O)O1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COC[C@H]1CN(c2noc3cc(OS(=O)(=O)C(F)(F)F)ccc23)C(=O)O1
Temperature: 0 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
8.4 ml (0.050 mol) of trifluoromethanesulphonic anhydride are added at 0° C. over 10 minutes to a solution of 11 g (0.042 mol) of (R)-5-(methoxymethyl)-3-(6-hydroxy-1,2-benzisoxazol-3-yl)oxazolidine-2-one in 110 ml of pyridine. The solution is stirred for 18 hours and then poured into ice-cold 2N aqueous hydrochloric acid solution. The product is extracted with ethyl acetate and then the organic phase is dried over sodium sulphate and concentrated under reduced pressure. 16.5 g of product are obtained.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:34]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1Cl)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-chlorophenyl isocyanate (0.147 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 167 mg (51.5%) of the desired product as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:34])[C:15]2[CH:20]=[C:19]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25](=[O:32])[NH:24][N:23]=3)[CH:18]=[CH:17][C:16]=2[F:33])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl>[F:33][C:16]1[CH:17]=[CH:18][C:19]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[NH:24][N:23]=2)=[CH:20][C:15]=1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Agent: Cl
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCNCC1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of industrial methylated spirits (IMS) (2200 ml) and concentrated HCl (4400 ml) was added compound C (2780.2 g) in portions at room temperature under nitrogen, the foaming was controlled by the addition rate. The solution was then stirred at 15 to 25° C. for 30 minutes and sampled for completion (HPLC).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O>>[Cl:9][CH2:10][C:11]1[N:8]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:7][CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccco1
Product: ClCc1coc(-c2ccco2)n1
Yield: 47 %

Procedure:
In substantially the same manner as in Reference Example 47, 2-furancarboxamide was aollowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(2-furyl)oxazole. The yield was 47%. Oily substance.
Reaction SMILES: C(N(CC)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C@H:16]([NH:18][CH2:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[OH:21])[CH3:17])=[O:5])C.[O:31]1CCOCC1>Cl>[Cl:28][C:24]1[CH:23]=[C:22]([C@@H:20]([OH:21])[CH2:19][NH:18][C@H:16]([CH3:17])[CH2:15][C:11]2[C:10]3[C:14](=[C:6]([C:4]([OH:31])=[O:5])[CH:7]=[CH:8][CH:9]=3)[NH:13][CH:12]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: C1COCCO1
Reactant: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12
Agent: Cl
Product: C[C@H](Cc1c[nH]c2c(C(=O)O)cccc12)NC[C@H](O)c1cccc(Cl)c1
Temperature: 150 °C
Yield: 30 %

Procedure:
A solution of 3-{(2 R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethyl-amino]propyl}-1H-indole-7-carboxylic acid diethylamide (175 mg, 0.41 mmol) in 1,4-dioxane (7 mL) and 6N hydrochloric acid (7 mL) is stirred with heating at 150° C. for 7 hours in a closed system. After cooling, the mixture is evaporated under reduced pressure to remove dioxane, and the resultant is neutralized with an aqueous Na2CO3 solution. The precipitates are filtered, and purified by reversed phase column (octa-decylsilyl, methanol/water=1/1→3/1) to give the desired 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethylamino]propyl}-1H-indole-7-carboxylic acid (45 mg, yield: 30%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH2:10][S:9][C@H:8]2[N:5]([C:6](=[O:23])[C@H:7]2[NH:11][C:12](=[S:22])[CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:24]([O-:26])=[O:25].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH2:10][S:9][C@H:8]2[N:5]([C:6](=[O:23])[C@H:7]2[NH:11][C:12](=[S:22])[CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:24]([OH:26])=[O:25]
Reactant: O=C([O-])C1=C(CCl)CS[C@@H]2[C@H](NC(=S)Cc3cc(Cl)ccc3Cl)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: O=C(O)C1=C(CCl)CS[C@@H]2[C@H](NC(=S)Cc3cc(Cl)ccc3Cl)C(=O)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A slurry of (6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)-thioacetamido]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylate, diphenylmethyl ester (10.0 g, 15.8 mmol) in CH2Cl2 (200 mL) at 0° C. was treated with anisole (24 mL) and then trifluoroacetic acid (80 mL). The resulting solution was stirred for 1 h at 0° C. and then concentrated under reduced pressure. The residue was stirred with Et2O, and the resulting solid was collected by filtration to give 5.20 g of (6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)-thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a white solid (70% yield), m.p. 125° C. 1H NMR (300 MHz, DMSO-d6) 67 3.51 (d, J=18 Hz, 1 H), 3.70 (d, J=18 Hz, 1 H), 3.91 (s, 2 H), 4.52 (d, J=11 Hz, 1 H), 4.58 (d, J=11 Hz, 1 H), 5.13 (d, J=5 Hz, 1 H), 5.70 (dd, J=5, 8 Hz, 1 H), 7.24 (dd, J=2, 8 Hz, 1 H), 7.47 (dd, t=2, 8 Hz, 2 H), 9.28 (d, J=8 Hz, 1 H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:16])=[C:12]([CH2:13][CH2:14]Cl)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C([O-])(=O)C([O-])=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:16])=[C:12]([CH2:13][CH2:14][N:29]3[CH2:28][CH2:27][CH:26]([C:23]4[C:22]5[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=5[O:25][N:24]=4)[CH2:31][CH2:30]3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCc2sc(C)c(CCCl)c2C1
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Product: CC(=O)N1CCc2sc(C)c(CCN3CCC(c4noc5cc(F)ccc45)CC3)c2C1
Yield: 14.5 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.0 g of 5-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.25 g of 5-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine as an oil, m.p. 198°-200° C. (decomposition) as an oxalate thereof.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.[CH2:23]([N:30]([CH2:34][CH2:35]Cl)[CH2:31][CH2:32]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([N:30]1[CH2:34][CH2:35][C:4]2([C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Br:1])[NH:6][C:5]2=[O:11])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: O=C1Cc2c(Br)cccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1Nc2cccc(Br)c2C12CCN(Cc1ccccc1)CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
A stirred solution of 4-bromoindolin-2-one (13.0 g, 61.3 mmol) in THF (500 mL) was treated by the dropwise addition of a 1.0M THF solution of NaHMDS (306 mL, 306 mmol) at −78° C. under nitrogen. After stirring at −78° C. for 30 minutes, N-benzylbis(2-chloroethyl)amine hydrochloride (18.05 g, 67.4 mmol) was added as a solid. The reaction mixture was stirred at −78° C. for 30 minutes and then allowed to warm to room temperature. The reaction mixture was then heated to reflux for 12 hours. After cooling to 0° C., the reaction was quenched by the addition of saturated aqueous NH4Cl solution. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×200 mL) The combined organics layers were washed with brine, dried with MgSO4 and concentrated under reduced pressure. The resulting solid was triturated with DCM/EtOAc to give 1′-benzyl-4-bromospiro[indoline-3,4′-piperidin]-2-one (19.3 g, 85%) as a solid. LCMS (APCI+) m/z 371/373 [M+H]+; Rt=2.71 min.
Reaction SMILES: OO.[N:3]1([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[N+:14]([O-:27])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH:21]([CH2:25][OH:26])[CH2:22]4)=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(O)(C(F)(F)F)=[O:29].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.N>C(Cl)Cl>[N:3]1([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[N+:14]([O-:27])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH:21]([CH2:25][OH:26])[CH2:22]4)=[CH:18][C:16]=3[N+:17]=2[O-:29])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: [O-][n+]1nc(CCCN2CCOCC2)nc2cc3c(cc21)CC(CO)C3
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: [O-][n+]1nc(CCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CC(CO)C3
Temperature: 20 °C
Reaction time: 17 h
Yield: 60.9 %

Procedure:
H2O2 (70%, 0.46 mL, 7.7 mmol) was added drop-wise (over 5 min) to a stirred solution of 1-oxide 140 (292 mg, 0.77 mmol), TFA (0.32 mL, 3.9 mmol), and TFAA (1.24 mL, 7.7 mmol) in DCM (25 mL) at 20° C. and the mixture stirred at 20° C. for 17 h. Another aliquot of H2O2 (70%, 0.46 mL, 7.7 mmol) and TFAA (1.24 mL, 7.7 mmol) were added and the mixture was stirred for 1 h. Aqueous NH3 solution (2 M, 30 mL) was added at 0° C. and the mixture stirred at 0° C. for 10 min, then stirred at 20° C. for 20 min. The mixture was extracted with DCM (5×80 mL), the combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1,4-dioxide 141 (169 mg, 61%) as a dull orange solid: mp (MeOH/DCM) 112-114° C.; 1H NMR δ 8.30 (s, 1H, H-9), 8.26 (s, 1H, H-5), 3.73 (d, J=6.4 Hz, 2H, CH2O), 3.45 (br s, 4H, 2×CH2O), 3.21-3.37 (m, 4H, H-8, CH2), 3.00-3.09 (m, 2H, CH2), 2.83-2.92 (m, 1H, H-7), 2.50 (t, J=6.4 Hz, 2H, CH2N), 2.39 (br s, 4H, 2×CH2N), 2.07-2.15 (m, 2H, CH2), OH not observed; 13C NMR [(CD3)2SO] δ 154.1, 153.7, 149.3, 138.7, 133.5, 115.3, 113.3, 66.0 (2), 63.4, 57.2, 53.0 (2), 41.5, 35.6, 35.1, 28.0, 21.0. HRMS (FAB+) calcd for C18H25N4O4 (MH+) m/z 361.1876, found 361.1878.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH3:16])[C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C([O-])(=O)C.[Na+]>O>[C:17]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([CH3:16])[C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1)(=[O:19])[CH3:18]
Reactant: Cc1nc(-c2ccc(N)cc2)c[nH]c1=O
Reactant: CC(=O)OC(C)=O
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(-c2c[nH]c(=O)c(C)n2)cc1

Procedure:
5-(4-Aminophenyl)-3-methyl-2(1H)-pyrazinone hydrobromide (1.0 g) in water (25 ml) was treated with acetic anhydride and sodium acetate in a similar manner to that described in Example 3. On recrystallisation from aqueous acetic acid the title compound (0.68 g) had m.p.>300° C.; δ(DMSO-d6) inter alia 2.08 (3H,s, CO--CH3), 2.39 (3H, d, 3-CH3), 10.0 (1H, s, NHCO); ν(Nujol mull) 1655 (C=0) cm-1.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:15](C(OC(C)(C)C)=O)[C:9]2=[N:10][C:11]([Br:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH2:2]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][C:11]([Br:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2ccc(Br)nc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2ccc(Br)nc2[nH]1
Yield: 89.2 %

Procedure:
The solution of 18.4 g (0.05 mol) 6-bromo-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 165 ml dichloromethane was cooled to 0 deg C. and then 38.0 ml trifluoroacetic acid was added within 5 min. The cooling bath was removed and after 2 h at room temperature the reaction mixture was poured into 500 ml saturated aqueous sodium bicarbonate solution. The organic layer was extracted three times with 150 ml dichloromethane. The combined organic phases were washed with 200 ml brine, dried over magnesium sulfate and filtered. The solvent was evaporated and the residue was dried under high vacuum to afford 12.0 g (95.5%) of the desired product as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.[CH3:46][S:47][CH2:48][CH2:49]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.[Cl-].[Na+].O>[F:43][C:40]([F:41])([F:42])[C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:49][CH2:48][S:47][CH3:46])=[CH:12][N:13]=1
Reactant: CSCCO
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCSC)cn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2-[(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-ol (300 mg) is dissolved in tetrahydrofuran (2 mL), and thereto are added 2-(methylthio)ethanol (162 μl) and triphenylphosphine (488 mg), and thereto is added dropwise a 40% diethyl azodicarboxylate/toluene solution (424 μl) under water-cooling, and the mixture is stirred at 50° C. overnight. Further thereto are added 2-(methylthio)ethanol (243 μl) and triphenylphosphine (244 mg), and thereto is added dropwise diisopropyl azodicarboxylate (361 μl) under water-cooling, and the mixture is stirred at 60° C. for 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=99:1→9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[5-(2-methylsulfanyl-ethoxy)-pyrimidin-2-yl]-amine (300 mg). MS (m/z): 718 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]1[NH:23][C:24](=[O:27])[CH2:25]I)=[O:12])=[CH:5]2.C(=O)([O-])[O-:29].[Na+].[Na+].O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]1[NH:23][C:24](=[O:27])[CH2:25][OH:29])=[O:12])=[CH:5]2
Reactant: O=C([O-])[O-]
Reactant: O=C(CI)NC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(CO)NC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 86.8 %

Procedure:
5-Chloro-N-{1-[(iodoacetyl)amino]-2,3-dihydro-1H-inden-2-yl}-1H-indole-2-carboxamide (Method 7a; 60 mg, 0.12 mmol) and sodium carbonate (100 mg) were dissolved in 1:1 dioxane:water (5 mL) and heated to reflux for 20 hours. The reaction was cooled, water (10 mL) added, filtered and the filter cake washed with water (3×1 mL) and dried to give the title compound (40 mg, 85%) as a white powder.