Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[CH:12]([C:19]2[N:20]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:21]=[C:22]3[C:27]=2[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:20]2[C:19]([CH:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)/[CH:11]=[CH:10]/[C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[CH:5][CH:6]=3)=[C:27]3[C:22]([CH2:23][CH2:24][CH2:25][CH2:26]3)=[N:21]2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(/C=C/C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(/C=C/C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1

Procedure:
In analogy to the procedure described in example 63.3, [rac]-4-{(E)-3-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3-cyclohexyl-propenyl}-benzoic acid methyl ester was treated with NaOH in MeOH to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[N:10]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)#[CH:26].C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[N:10]=2)=[C:2]([C:26]#[C:25][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH:7]=1
Reactant: Clc1ccc(-c2nc3ccccc3n2CC2CCCCC2)c(Br)c1
Reactant: C#Cc1ccc(C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(C#Cc2cc(Cl)ccc2-c2nc3ccccc3n2CC2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a solution of 2-(2-bromo-4-chloro-phenyl)-1-cyclohexylmethyl-1H-benzoimidazole (0.56 g, 1.38 mmol) in dry tetrahydrofuran (8 ml) were added 4-ethynyl-benzonitrile (0.22 mg, 1.7 mmol; CAS Reg. No. 3032-92-6), bis(triphenylphosphine)palladium(ii) dichloride (63 mg, 0.09 mmol), copper(I) iodide (8 mg, 0.04 mmol) and triethyl amine (10 ml) at 25° C. in a sealed tube. The resulting mixture was degassed and back-filled with nitrogen three times. It was then allowed to stir at 80° C. for 16 h. The reaction mixture was filtered through a bed of celite, concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (20-25 ethyl acetate/n-hexane) to afford the desired compound as an off-white powder (38%). MS (Turbo Spray): m/z=450.0 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C:12]34[C:15]5[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:16]=5[O:17][CH:11]3[C:10](=O)[CH2:9][CH2:8][CH:7]4[CH2:6]2)[CH2:3][CH2:2]1.[CH2:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C:12]34[C:15]5[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:16]=5[O:17][CH:11]3[CH:10]([CH3:25])[CH2:9][CH2:8][CH:7]4[CH2:6]2)[CH2:3][CH2:2]1
Reactant: COc1cccc2c1OC1C(=O)CCC3CN(CC4CC4)CCC231
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1cccc2c1OC1C(C)CCC3CN(CC4CC4)CCC231

Procedure:
Oxidation of XI ##STR97## with chromium trioxide gives 3-cyclopropylmethyl-9-methoxy-2,4,4a,5,6,7-hexahydro-1H-benzo[4,5]furo[3,2-e]isoquinolin-7[3H]-one ##STR98## Reaction of this compound with methylenetriphenylphosphorane followed by catalytic hydrogenation of the resulting 7-methylene derivative gives 3-cyclopropylmethyl-9-methoxy-7-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline ##STR99##
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.ClC(OC(Cl)C)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]([C:20]([F:23])([F:21])[F:22])=[N:18][N:19]=2)[CH2:10][CH2:9]1
Reactant: FC(F)(F)c1nnc(NC2CCN(Cc3ccccc3)CC2)s1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: FC(F)(F)c1nnc(NC2CCNCC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a stirred solution of (1-benzyl-piperidin-4-yl)-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amine (D3) (0.50 g, 1.46 mmol) and diisopropylethylamine (0.76 ml, 4.38 mmol) in dichloromethane (20 ml) at 0° C., was added 1-chloroethyl chloroformate (0.47 ml, 4.38 mmol). The reaction mixture was stirred at room temperature for 2 h. and after this period, the solvent evaporated in vacuo. The crude product was dissolved in methanol (30 ml) and the reaction mixture was stirred at reflux for 1.5 h. After evaporation of the solvent, the crude product was dissolved in water and extracted with diethyl ether (2×25 ml) and dichloromethane (3×25 ml). The aqueous layer was separated and evaporated in vacuo. The crude product was purified by reverse phase HPLC. The desired fractions were collected and evaporated in vacuo to yield D4 (0.29 g, 79%) as a solid. C8H11F3N4S requires 252. Found 253 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[OH:27]/[N:26]=[C:9](/[C:11]1[CH:12]=[CH:13][C:14](=[O:18])[N:15]([CH3:17])[CH:16]=1)\[CH2:8][CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccccc2)c2ccccc2)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccccc2)c2ccccc2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3,3-diphenyl-propionyl)-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI+): m/z=333.3 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[C:12]([O:33][CH2:34][CH3:35])=[C:13]([CH:19]2[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:20]2)[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1.C(Cl)Cl>>[ClH:17].[NH2:8][CH:9]([C:11]1[C:12]([O:33][CH2:34][CH3:35])=[C:13]([CH:19]2[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:20]2)[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10]
Reactant: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1

Procedure:
Benzyl 3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate (65 mg, 0.13 mmol, second peak from chiral separation in previous step) was treated with 4.0 M HCl in dioxane (0.4 mL, 2 mmol) in methylene chloride (0.4 mL, 6 mmol) at room temperature for 2 hours. The reaction mixture was evaporated to dryness to give benzyl 3-[3-[1-aminoethyl]-5-chloro-2-ethoxy-6-methylphenyl]azetidine-1-carboxylate hydrochloride. LCMS calculated for C22H28ClN2O3 (M+H)+: m/z=4012. found: 403.1. A mixture of the above HCl salt, 6-bromo-9H-purine (31 mg, 0.16 mmol) and DIPEA (0.11 mL, 0.65 mmol) in ethanol (1 mL) was heated at 100° C. overnight. The mixture was diluted with sat. NaHCO3 solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (83 mg). LCMS calculated for C27H30ClN6O3 (M+H)+: m/z=521.2. found: 521.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=O)[CH2:15][CH2:16][CH:17]1[CH2:20][CH:19]([N:21]([CH2:25][C@@H:26]2[C@@H:33]3[C@@H:29]([O:30][C:31]([CH3:35])([CH3:34])[O:32]3)[C@H:28]([N:36]3[C:40]4[N:41]=[CH:42][N:43]=[C:44]([NH:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=5[O:55][CH3:56])[C:39]=4[CH:38]=[CH:37]3)[CH2:27]2)[CH:22]([CH3:24])[CH3:23])[CH2:18]1>CC(O)=O>[CH3:56][O:55][C:48]1[CH:49]=[C:50]([O:53][CH3:54])[CH:51]=[CH:52][C:47]=1[CH2:46][NH:45][C:44]1[C:39]2[CH:38]=[CH:37][N:36]([C@H:28]3[C@H:29]4[C@H:33]([O:32][C:31]([CH3:34])([CH3:35])[O:30]4)[C@@H:26]([CH2:25][N:21]([CH:22]([CH3:23])[CH3:24])[CH:19]4[CH2:20][CH:17]([CH2:16][CH2:15][C:14]5[NH:13][C:3]6[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:10])[F:12])=[CH:7][C:2]=6[N:1]=5)[CH2:18]4)[CH2:27]3)[C:40]=2[N:41]=[CH:42][N:43]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)Nc4ccc(OC(F)(F)F)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(OC(F)(F)F)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1

Procedure:
N-(2-amino-4-(trifluoromethoxy)phenyl)-3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanamide (1.4 g, 1.8 mmol) was heated in AcOH at 60° C. overnight. The reaction mixture was concentrated in vacuo giving the crude product.
Reaction SMILES: [OH2:1].[OH-].[Li+].[CH3:4][C@H:5]([O:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16](CC([O-])=O)=[C:15]([N:26]([CH3:28])[CH3:27])[CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl>C1COCC1.O>[CH3:4][C@H:5]([O:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([OH:1])=[C:15]([N:26]([CH3:28])[CH3:27])[CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O
Reactant: CCCCCC[C@H](C)Oc1cc(N(C)C)c(CC(=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCC[C@H](C)Oc1cc(N(C)C)c(O)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 92 %

Procedure:
Lithium hydroxide monohydrate (226 mg, 5.38 mmol) was added to a stirred solution of compound 59 in 15 ml THF and 5 ml water. The reaction mixture was stirred for 15 minutes and was then acidified with concentrated HCl. Extracted with ether, the organic layer was washed with brine and dried over MgSO4. The crude product was purified via flash chromatography over silica gel (80/20, v/v, Hex/EtOAc). Evaporation of solvent yielded 308 mg (92%) of a viscous orange oil. This product rapidly decomposes in chloroform and should be carried on immediately to the next step.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[O:11][CH3:12].[Cl:13][S:14](O)(=[O:16])=[O:15]>ClCCl>[CH3:12][O:11][C:3]1[C:4]([CH3:10])=[C:5]([CH3:9])[C:6]([S:14]([Cl:13])(=[O:16])=[O:15])=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: COc1c(C)c(C)cc(C)c1C
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1c(C)c(C)c(S(=O)(=O)Cl)c(C)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In 600 ml of dichloromethane was dissolved 10.0 g of 2,3,5,6-tetramethylanisole, followed by addition of a solution (400 ml) of 12 ml of chlorosulfonic acid in dichloromethane at -5°~-10° C. The mixture was kept stirred for 2 hours and the reaction mixture was poured into ice-5% aqueous NaHCO3. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off and the residue was crystallized from n-hexane and filtered.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:23]([F:26])([F:25])[F:24])[C:18]([O:20][CH2:21][CH3:22])=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:40]=[C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH2:14][C:13](=[O:15])[NH:12][C:11]4[CH:16]=[C:17]([C:23]([F:26])([F:25])[F:24])[C:18]([O:20][CH2:21][CH3:22])=[CH:19][C:10]=4[N:9]=3)[CH:3]=2)[CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c1)=N2

Procedure:
The title compound was prepared from 4-(3-bromo-phenyl)-7-ethoxy-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example B.3) (200 mg, 0.50 mmol) and commercially available 3-tert-butylsulfamoyl-benzeneboronic acid [CAS-no. 221290-14-8] (144 mg, 0.55 mmol) according to the general procedure II. Obtained as an off-white solid (169 mg, 65%). MS (ISP) 559.7 [(M+H)+]; mp 215-218° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:21]([O:24][C@@H:25]([CH3:29])[C:26](Cl)=[O:27])(=[O:23])[CH3:22]>>[C:21]([O:24][C@@H:25]([CH3:29])[C:26]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)=[O:13])=[O:27])(=[O:23])[CH3:22]
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: CC(=O)O[C@@H](C)C(=O)Nc1c(C(=O)c2cc(C)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-methylpyridine-2-carbonyl)indole (Example 70) and (S)-(−)-2-acetoxypropionyl chloride. m.p.: 213-214° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:19](=[O:22])(=[O:21])[NH2:20])[C:12]=1[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:7]([OH:9])=[O:8])([O-])=O.[OH-].[Li+].[H][H]>O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:19](=[O:21])(=[O:22])[NH2:20])[C:12]=1[O:13][CH2:14][C:15]([F:17])([F:16])[F:18])[C:7]([OH:9])=[O:8]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1OCC(F)(F)F
Reactant: [H][H]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1OCC(F)(F)F

Procedure:
3-Nitro-5-sulphamyl-4-(β,β,β-trifluoroethoxy)-benzoic acid (2 g) in water (30 ml) was adjusted to a pH of 9 by addition of lithium hydroxide, and the resulting solution was hydrogenated at room temperature and at a hydrogen pressure of 1.1 atmospheres after addition of Pd-on-carbon catalyst (0.2 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the 3-amino-5-sulphamyl-4-(β ,β ,β-trifluoroethoxy)-benzoic acid was precipitated from the filtrate by addition of 4N hydrochloric acid until a pH of 2.5. After recrystallization from aqueous ethanol and drying, the melting point of the compound was 253°-254°C.
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])[CH2:2][CH2:3][CH3:4].[S:12]1[C:16]([CH:17]=O)=[CH:15][N:14]=[CH:13]1>>[CH2:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][CH2:17][C:16]1[S:12][CH:13]=[N:14][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccccc1N
Reactant: O=Cc1cncs1
Product: CCCCc1ccccc1NCc1cncs1

Procedure:
The desired compound was prepared according to the method of Example 403H starting with 2-butylaniline and the aldehyde from Example 1202A. m/e (DCI) 247 (MH+)
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1>>[Si:28]([O:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:8])([CH3:9])[N:5]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=1)([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccncc2)[C@@H](CO)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccncc2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C

Procedure:
The title compound was synthesized in manner analogous to that described in Example 407, using (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(pyridin-4-ylmethyl)oxazolidine-3-carboxylate in the presence of TBSCl and imidazole, and was used without further purification.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])[NH2:32]>>[CH3:37][O:36][CH2:35][CH2:34][O:33][C:31]1[N:32]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:30]=1
Reactant: COCCOC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: COCCOc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 1, 300 mg (0.717 mmol) of the compound from Example 9A and 480 mg (2.15 mmol, purity 60%) of 2-methoxyethyl N′-hydroxyimidocarbamate from Example 44A were reacted. Yield: 65 mg (17% of theory).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCN1CCc2ccccc21
Product: CCN1CCc2cc(S(=O)(=O)Cl)ccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
1-ethylindoline (15 g, 102.04 mmol) was added at 0° C. to ClSO3H (60 g). The resulting solution was stirred at 50° C. overnight, then the reaction was quenched by adding 300 g iced water. The resulting solution was extracted with dichloromethane (3×600 mL) and the organic layers were combined, dried (MgSO4) and concentrated. The residue was then purified by column chromatography using a 1:100 ethyl acetate/petroleum ether solvent system to give 1.5 g (6%) of 1-ethylindoline-5-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.28 (d, 1H), 7.18 (d, 1H), 7.11 (s, 1H), 3.39 (q, 2H), 3.52 (t, 2H), 3.06 (t, 2H), 1.23 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2O.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:5]1[C:4]2[C:9](=[CH:10][N:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:12]#[N:13]
Reactant: N#Cc1cnc2cnc(Cl)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc2cnc(Cl)cc2c1Cl

Procedure:
To 650 mg of 6-chloro-4-hydroxy-[1,7]naphthyridine-3-carbonitrile under an inert atmosphere was added 20 mL of phosphorous oxychloride. After two hours at reflux, the excess phosphorous oxychloride was removed in vacuo and ice-water and chloroform were added. Solid potassium carbonate was then added carefully to a pH of about 8. The chloroform layer was washed with brine, dried with sodium sulfate, and stripped to give a crude product. This material was further purified by passing it through a plug of silica gel with 5% ethyl acetate/chloroform to give approximately 600 mg of 4,6-dichloro-[1,7]naphthyridine-3-carbonitrile as a yellowish solid, which was used in the following step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[N:13]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:12]=2)[CH:3]=1.[N-:48]=[C:49]=[O:50].[K+]>O.C(O)(=O)C>[CH3:39][C:36]1[CH:37]=[CH:38][N:25]2[C:26]=1[C:27](=[O:35])[N:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]([C@@H:21]([NH:20][C:18]1[C:19]3[C:11]([C:4]4[CH:3]=[C:2]([NH:1][C:49]([NH2:48])=[O:50])[CH:10]=[C:9]5[C:5]=4[CH:6]=[CH:7][NH:8]5)=[CH:12][N:13]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[C:14]=3[N:15]=[CH:16][N:17]=1)[CH3:22])=[N:24]2
Reactant: [N-]=C=O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NC(N)=O)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 72.6 %

Procedure:
To a suspension of (S)-2-(1-((5-(6-amino-1H-indol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) in 403 μl water and 208 μl acetic acid was added potassium isocyanate (17 mg, 0.21 mmol) according to the method described in Preparation 181. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 40 mg (75% yield) of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:12]1=[O:13].[C:30]([O:36][CH2:37]Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CC(C)=O>[C:24]1([N:14]2[C:12](=[O:13])[C:11]([CH2:10][CH2:9][CH2:8][CH3:7])([CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:16](=[O:17])[N:15]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC1(COC(=O)C(C)(C)C)C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Yield: 5 %

Procedure:
Potassium carbonate (2.26 g, 0.016 mole) was suspended in an acetone (125 ml) solution of phenylbutazone and the suspension was refluxed overnight. The next day pivalyloxymethyl chloride (4.99 g, 0.033 mole) was added to the resulting solution and the solution was refluxed overnight. The suspension was cooled and filtered; the residue (2.00 g, 83%) was potassium chloride. The filtrate was concentrated in vacuo and the residue was suspended in ether, then filtered. The residue was washed with ether until the washings did not contain any product by TLC. The residue from the ether suspension was the potassium salt of phenylbutazone (2.25 g, 20%). The ether was then concentrated in vacuo and the residue was absorbed on silica gel and chromatographed on neutral silica gel (CC-7, Mallinckrodt) using petroleum ether bp 30-60° C - ether (1:1) as the eluent to give two fractions. The first fraction (Rf 0.46, silica gel, heptane-ether, 1:1) was crystallized from heptane-petroleum ether bp 30-60° C, 1:1 to give 0.63 g (mp 116- 117° C, 5% yield) of 1,2-diphenyl-4-butyl-4-pivalyloxymethyl-3,5-pyrazolidinedione. nmr (CDCl3) δ 4.40 (S, 2, ##STR11##
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:8]([CH2:11][C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:13][C:12]([N+:14]([O-:16])=[O:15])([CH3:17])[CH2:11][C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)[C:3]2=[N:10][CH:9]=1
Reactant: CC(C)(Cc1cnc2c(Br)cccn12)[N+](=O)[O-]
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(Cc1cnc2c(-c3cccs3)cccn12)[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
A mixture of 8-bromo-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (1.5 g, 5.0 mmol), Pd(PPh3)4 (0.68 g), 2M aqueous sodium carbonate solution (8 ml), and dioxane (68 ml) is stirred for 30 minutes under an atmosphere of argon. After addition of thiophene-2-boronic acid (0.96 g, 7.5 mmol), the mixture is stirred overnight at 80° C. The solids are removed by filtration, and the residue is chromatographed (silica gel, dichloromethane/ethanol 95:5) to give 1.52 g of 3-(2-methyl-2-nitropropyl)-8-(2-thienyl) imidazo[1,2-a]pyridine (100%).