Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2oc3ccccc3c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2oc3ccccc3c2c1
Yield: 134.3 %

Procedure:
In a Parr hydrogenation bottle, 10% Pd/C (0.77 g, 0.724 mmol) was added and the bottle purged with nitrogen. Next 2-nitrodibenzo[b,d]furan (15 g, 44.3 mmol) in 180 mL of ethyl acetate was added and the mixture was hydrogenated on a Parr Hydrogenator until no more hydrogen is taken up by the solution. The catalyst was filtered off through Celite and washed with ethyl acetate. The filtrate was evaporated and pre-absorbed onto Celite. The Celite mixture was purified using a Varian 400 g column eluting with dichloromethane. 10.9 g of product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(Cl)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A mixture of ethyl 5-(4-chlorophenyl)thiophene-2-carboxylate (1.05 g, 3.94 mmol), methanol (40 ml) and 1.0 M aq NaOH (15.75 ml, 15.75 mmol) was stirred at reflux for 6 hours. Upon cooling to RT, the reaction was acidified to pH 3 with conc. HCl and extracted with EtOAc (60 ml). The EtOAc layer was dried over Na2SO4 and concentrated to yield 5-(4-chlorophenyl)thiophene-2-carboxylic acid (902 mg, 3.78 mmol, 96% yield) as an off-white solid. LC MS at t=2.44 min. (m+H=240) PHENOMENEX® S5 C18 4.6×30 mm column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient over 2 min at 5 mL/min with 1 min hold at the end of the gradient. 1H NMR (400 MHz, DMSO) δ ppm 7.36-7.97 (m, 6H), 13.19 (s, 1H).
Reaction SMILES: N[N:2]1[C:7](=[O:8])[C:6]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[C:5]=2[NH:4][C:3]1=[O:17].N([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][C:6]3[C:7](=[O:8])[NH:2][C:3](=[O:17])[NH:4][C:5]=3[C:11]=2[CH:12]=1
Reactant: Nn1c(=O)[nH]c2c(oc3ccc(Cl)cc32)c1=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2oc3ccc(Cl)cc3c2[nH]1
Temperature: 47.5 °C
Yield: 89.3 %

Procedure:
To a suspension of 3-amino-8-chloro-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione (2.9 g, 11.6 mmol) in 1:1 mixture of acetic acid/H2O (200 mL) was added NaNO2 (2.5 g, 36.0 mmol). The reaction mixture was heated at 45-50° C. until the evolution of brown fumes ceased (2 h). The product was collected by filtration to afford 2.45 g (89%) of the desired product.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH:3]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[CH2:4][C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl.CN(C=O)C>[CH3:17][CH:2]([CH:3]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:5](=[O:7])[CH2:4]1)[CH3:1]
Reactant: COc1cccc(CC(CC(=O)O)C(C)C)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(C(C)C)CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a solution of 4-methyl-3-{[3-(methyloxy)phenyl]methyl}pentanoic acid (67) (0.15 g, 0.63 mmol) in CH2Cl2 (5 mL) was added oxalyl chloride (0.17 mL, 1.90 mmol) followed by one drop of DMF. The mixture was stirred at room temperature overnight. CH2Cl2 and excess of oxalyl chloride were removed under vacuum. The residue was dissolved in CH2Cl2 (10 mL), cooled in an ice bath, AlCl3 (0.13 g, 0.95 mmol) was added. The resulting mixture was stirred at 0° C. for 4 h. Poured into 1 N HCl (7 mL) with ice, and the mixture was extracted with CH2Cl2. The extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (8:1) to give 0.112 g (81%) of the title compound (68) as a light yellow viscous oil, which solidified after standing. 1H NMR (400 MHz, CDCl3): δ 0.97 (d, J=6.8 Hz, 3H), 0.98 (d, J=6.7 Hz, 3H), 1.60-1.70 (m, 1H), 1.90-2.05 (m, 1H), 2.30 (dd, J1=16.5 Hz, J2=2.8 Hz, 1H), 2.65-2.80 (m, 1H), 2.85-2.95 (m, 1H), 3.85 (s, 3H), 6.71 (d, J=2.2 Hz, 1H), 6.81 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].[CH2:25]([NH2:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([NH:33][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:21]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Reactant: NCCc1ccccc1
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and phenethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.90 (1H, br), 10.65 (1H br), 8.30 (1H, br), 7.37-7.22 (1H, m), 4.04 (2H, br s), 3.53 (2H, m, J˜5 Hz), 2.83 (2H, t, J=7 Hz); Anal. Calcd for C24H21N3O3.0.25 CH2Cl2: C, 69.45; H, 5.12; N, 9.92. Found: C, 69.40; H, 4.92; N, 10.11.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[Li+].CC([N-]C(C)C)C.C1([O-])C=CC=CC=1.Cl[CH2:29][C:30]([O:32][CH3:33])=[O:31].Cl>C1(C)C=CC=CC=1.O>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH3:12]
Reactant: CCN(CC)c1cccc(O)c1
Reactant: COC(=O)CCl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)c1cccc(OCC(=O)OC)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
5.0 g (30 mmol) of 3-diethylaminophenol are dissolved in 80 ml dry toluene and cooled down to -78° C. Within 15 min 15 ml of a 2 molar LDA-solution are added. After warming up to room temperature this phenolate solution is added in dropwise to a solution of 2.7 ml (30 mmol) of methyl chloroacetate in 15 ml of dry toluene. The dark brown reaction mixture is stirred at room temperature for 3 hours, after then it is added to 300 ml of water. Then solution is made acidic by adding a little amount of 2 N HCl. Afterwards, the reaction mixture is extracted three times with 80 ml of chloroform each time. The organic phases are collected and are dried with MgSO4. After the drying agent is filtered off, the solvent has been stripped off on a rotary evaporator, a dark brown, highly viscous residue is obtained. Fractional distillation under the reduced atmosphere of an oil pump yields the analytically pure, slightly yellowish, viscous, liquid product, which quickly turns dark brown under the influence of light and air.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[C:10]3[CH2:9][N+:8]([O-])=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:6]=2[CH:28]=1.O1CCCC1>[Ni].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[C:10]3[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:6]=2[CH:28]=1
Reactant: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-n2cnc(N3CCCC3)c2C1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: Fc1ccccc1C1=NCc2c(N3CCCC3)ncn2-c2ccc(Cl)cc21
Reaction time: 15 h

Procedure:
A mixture of 1 g of 8-chloro-6-(2-fluorophenyl)-3-pyrolidinyl-4H-imidazo[1,5-a][1,4]benzodiazepine 5-oxide, 5 g of Raney nickel, 25 ml of tetrahydrofuran and 25 ml of ethanol was hydrogenated at atmospheric pressure for 15 hours. The catalyst was removed by filtration over Celite and the filtrate was evaporated. The residue was passed over silica gel using 5% (v/v) of ethanol in methylene chloride. Crystallization from ether/hexane gave end product as yellowish crystals with mp 114°-118° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C1COCC1>[O-:24][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc[n+]([O-])c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
To a mixture of 4-tolylboronic acid (38 g, 0.28 mol), 3-bromopyridine (44 g, 0.28 mol), Na2CO3 (200 g) in toluene (500 ml) and water (500 ml) was added Pd(PPh3)4 (16 g, 0.014 mol), and refluxed for 16 h. The reaction mixture was cooled, and the separated organic layer was washed with water and brine, and dried. The solvent was removed to give 4-(3-pyridyl)toluene (42 g, 90%). To a mixture of 4-(3-pyridyl)toluene (35 g, 0.207 mol) in pyridine (400 ml) and water (400 ml) was added KMnO4 (163 g, 1.03 mol) in portions and refluxed for 12 h. The reaction mixture was filtered through celite and acidified with conc. HCl. The product was washed with water and dried to give 4-(3-pyridyl)benzoic acid (32 g, 76%) as a white solid. To a mixture of 4-(3-pyridyl)benzoic acid (22 g, 0.11 mol) in THF (2.51), mCPBA (152 g, 0.44 mol, 50%) was added and stirred at RT for 12 h. The solid was filtered, and washed with THF to give 4-(1-oxido-3-pyridinyl)benzoic acid (20 g, 86%).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][C:9]([CH:11]([O:14][NH2:15])[CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28](=O)[C:29]([OH:31])=[O:30])[N:27]=1>CN(C)C=O.ClCCl>[NH2:22][C:23]1[S:24][CH:25]=[C:26](/[C:28](=[N:15]/[O:14][CH:11]([C:9]([O:8][CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])[CH2:12][CH3:13])/[C:29]([OH:31])=[O:30])[N:27]=1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Reactant: CCC(ON)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
30 g of O-(1-diphenylmethoxycarbonylpropyl)hydroxylamine and 16.2 g of (2-amino-4-thiazolyl)glyoxylic acid are stirred for 1 hour at room temperature in 60 ml of dimethylformamide. The reaction mixture is diluted with dichloromethane, and washed with 2N hydrochloric acid and several times with water. After evaporating the dichloromethane phase, 41 g of the title compound remain as a solid residue.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[CH:16]=[C:15]3[CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=2[O:32][CH3:33])=[O:8])[CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH2:44])(=[O:43])=[O:42]>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[CH:16]=[C:15]3[CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH:44][S:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[Cl:34])(=[O:43])=[O:42])=[O:29])=[CH:25][C:24]=2[O:32][CH3:33])=[O:8])[CH2:5][CH2:6]1
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(CCNC(=O)N3CCOCC3)cc12
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2Cl)ccc1Cc1cn(C)c2ccc(CCNC(=O)N3CCOCC3)cc12

Procedure:
Using a similar procedure to that described in Example 2, part c, except starting from 4-[5-[2-[(morpholinocarbonyl)amino]ethyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoic acid, and using 2-chlorophenylsulfonamide instead of 2-methylphenylsulfonamide, the title compound was obtained (45%) as a white solid; mp 175°-181° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.OO.N[C:14](N)=[O:15]>C(Cl)Cl>[Br:1][C:2]1[C:7]([O:15][CH3:14])=[N:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Br)cn1
Reactant: NC(N)=O
Agent: OO
Solvent: ClCCl
Product: CCOc1ccc(Br)c(OC)n1
Temperature: 25 °C

Procedure:
To 5.00 g (24.7 mmol) 5-bromo-2-ethoxy-pyridine in 50 mL DCM are added 4.66 g (49.5 mmol) urea hydrogen peroxide. Then the mixture is chilled to 0° C. before 6.88 mL (49.5 mmol) TFA anhydride are added. Afterwards cooling is removed and the resulting mixture is stirred over night while the temperature raises to r.t. The solvent is removed in vacuo, water is added and the resulting mixture is extracted with DCM. The combined org. layers are dried over MgSO4, filtered and the sovent is removed in vacuo. The crude product is purified by column chromatography (silica gel, DCM/MeOH).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:35][C:36]1[CH:41]=[CH:40][C:39]([C@@H:42]([OH:45])[CH2:43][NH2:44])=[CH:38][C:37]=1[NH:46][S:47]([CH3:50])(=[O:49])=[O:48])C1C=CC=CC=1>>[OH:45][C@H:42]([C:39]1[CH:40]=[CH:41][C:36]([OH:35])=[C:37]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:38]=1)[CH2:43][NH:44][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1OCc1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-methanesulfonamide (which was obtained in Example 8) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.70 (m, 2H), 1.90-2.10 (m, 2H), 2.06 (s, 3H), 2.50-2.65 (m, 2H), 2.90-3.15 (m, 3H), 2.94 (s, 3H), 3.55-3.70 (m, 2H), 4.65-4.80 (m, 1H), 6.79 (d, J=9.0 Hz, 2H), 6.97 (d, J=9.0 Hz, 2H), 7.00 (d, J=8.0 Hz, 1H), 7.06 (dd, J=8.0, 1.2 Hz, 1H), 7.22 (d, J=1.2 Hz, 1H), 7.40 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H), 10.42 (s, 1H), 10.44 (s, 1H); MS (ES) m/z: 618.0 (MH+); HRMS Calcd. for C28H36N5O7S2 (MH+): 618.2056. Found: 618.2056.
Reaction SMILES: [C:1]1([CH:7]([C:11](O)=[O:12])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.C1COCC1>[OH:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][OH:12]
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5.11 g of phenylmalonic acid in 50 mL of ether cooled to 0° C. was added 60 mL of a 1M solution of lithium aluminum hydride in THF. After stirring the mixture at room temperature overnight, the excess lithium aluminum hydride was quenched with ethyl acetate and dilute hydrochloric acid. The 1,3-dihydroxy-2-phenylpropane was isolated by ether extraction, and subsequent purification by flash chromatography gave 1.34 g of product characterized by NMR. This is treated with one equivalent of tosyl chloride in pyridine to afford the monotosylate. The purified monotosylate is heated in acetone with excess sodium iodide (as described in Example 23) to produce the 1-iodo-2-phenyl-3-propanol. Subsequent silylation with trimethylsilyltriflate (as in Example 16) and treatment of the iodosilylether with triphenylphosphine in toluene at 100 ° C. gives the title compound, which is characterized by its NMR and mass spectra.
Reaction SMILES: [SiH:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[C:8]([O:11][CH:12]=[CH2:13])(=[O:10])[CH3:9].CCOC(C)=O>C1(C)C=CC=CC=1.C1CCCCC1>[CH2:2]([Si:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:13][CH2:12][O:11][C:8](=[O:10])[CH3:9])[CH3:3]
Reactant: CC[SiH](CC)CC
Reactant: C=COC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC[Si](CC)(CC)CCOC(C)=O
Reaction time: 0.08 h

Procedure:
To a solution of 6.39 mL (40 mmol) of Et3SiH and 3.69 mL (40 mmol) of vinyl acetate in 40 mL of toluene is added 61.3 mg (0.16 mmol) of Rh2Cl2 (CO)4. Caution: the reaction evolves heat and gas. Within about 5 min, the reaction mixture darkens in color. Reaction is judged complete by TLC analysis (10% EtOAc in cyclohexane) after 1 h. The reaction is worked up and purified, if desired, as in example 1a.
Reaction SMILES: [NH2:1]/[C:2](=[N:14]\[OH:15])/[C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])[CH3:4].[CH2:16](OC(OCC)OCC)C.FC(F)(F)C(O)=O.CO>C(#N)C.O>[O:15]1[CH:16]=[N:1][C:2]([C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])([CH3:5])[CH3:4])=[N:14]1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)NC(C)(C)/C(N)=N/O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(C)(C)c1ncon1
Temperature: 50 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of (Z)-tert-butyl 1-amino-1-(hydroxyimino)-2-methylpropan-2-ylcarbamate (Example 33 b, 2 g, 9.2 mmol) in acetonitrile (10 mL) was added triethoxymethane (CAN 122-51-0, 4.8 mL) and trifluoroacetic acid (CAN 76-05-1, 0.1 mL). The mixture was heated to 50° C. and stirred overnight. The reaction mixture was added to methanol (10 mL) and water (10 mL). After evaporation of solvents, the residue was purified by column chromatography (silica gel, 60 g, eluting with 30% to 50% ethyl acetate in petroleum ether) to give the target product (0.668 g, 32%) MS (EI): m/e=250.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH2:14][CH2:13]3)[CH:4]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].CCOC(C)=O.O>C1COCC1>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([O:9][C:5]4[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[CH:7][N:6]=4)=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)=[O:31])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CNc1cc(Oc2ccc3c(c2)CCN3)ncn1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CNc1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2ccc(C(C)(C)C)cc2)ncn1

Procedure:
A solution of 70 mg (0.3 mMol) 5-(6-methylamino-pyrimidin-4-yloxy)-2,3-dihydro-indole (Step 21.2) and 70 mg (0.4 mMol) 4-tert.butyl-phenylisocyanat in 2 ml THF is stirred for 75 min at rt. The reaction mixture is dissolved with EtOAc and water, the aqueous layer separated off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; EtOAc/hexane 1:1→3:1→4:1) gives the title compound: MS: [M+1]+=418; TLC(EtOAc): Rf=0.20.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]1[SH:20])[CH3:8].CI>CN(C=O)C>[CH2:7]([N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[N:11]=[C:10]1[S:20][CH3:1])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CCn1c(S)nc(C(F)(F)F)cc1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCn1c(SC)nc(C(F)(F)F)cc1=O
Yield: 94.2 %

Procedure:
Next, potassium carbonate (8.15 g, 59.0 mmol) was added to DMF (100 ml) solution of 3-ethyl-2-mercapto-6-trifluoromethyl-4(3H)-pyrimidinone (11.0 g, 49.0 mmol), methyl iodide (3.68 ml, 59.0 mmol) was added with stirring under ice-cooling, followed by stirring for 4 hours while gradually returning to room temperature. After completion of the reaction, the reaction solution was concentrated under a reduced pressure, water (100 ml) and ethyl acetate (100 ml) were added to the thus obtained residue to separate the organic layer, and then the aqueous layer was extracted with ethyl acetate (50 ml×3). The organic layers were combined, washed with water (100 ml×3) and saturated brine (300 ml) and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the resulting filtrate was concentrated under a reduced pressure to obtain 3-ethyl-2-methylthio-6-trifluoromethyl-4(3H)-pyrimidinone (11.0 g, 94%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[I:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][C:22]1[CH:26]=[CH:25][S:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[I:12][C:13]1[CH:14]=[N+:15]([O-:9])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][C:22]1[CH:26]=[CH:25][S:24][CH:23]=1
Reactant: Ic1cnccc1OCCc1ccsc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1ccc(OCCc2ccsc2)c(I)c1
Reaction time: 18 h
Yield: 96.3 %

Procedure:
m-Chloroperbenzoic acid (1.55 g, 6.29 mmol) was added portionwise to a solution of 1.0 g (3.02 mmol) of 3-iodo-4-(2-(thiophen-3-yl)ethoxy)pyridine in 150 ml of methylene chloride. The mixture was stirred for 18 hours then mixed with 100 ml of 1 M aqueous sodium carbonate. The organic layer was separated and the aqueous one was extracted 2 times with 10 ml of methylene chloride. Combined organic extracts were washed with brine and dried over sodium sulfate. The solution was concentrated in vacuum to give 3-iodo-4-(2-(thiophen-3-yl)ethoxy)pyridine 1-oxide (1.01 g, 92%). MS: (ESI+) 348.0
Reaction SMILES: CS(OCC1C(C2C=CC(OC)=CC=2)=CSC=1C(F)(F)F)(=O)=O.FC1C=C(O)C=C(F)C=1CCC(OCC)=O.[F:40][C:41]1[CH:42]=[C:43]([CH2:67][CH2:68][C:69]([O:71]CC)=[O:70])[CH:44]=[C:45]([F:66])[C:46]=1[O:47][CH2:48][C:49]1[C:53]([C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=2)=[CH:52][S:51][C:50]=1[C:62]([F:65])([F:64])[F:63]>>[F:40][C:41]1[CH:42]=[C:43]([CH2:67][CH2:68][C:69]([OH:71])=[O:70])[CH:44]=[C:45]([F:66])[C:46]=1[O:47][CH2:48][C:49]1[C:53]([C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=2)=[CH:52][S:51][C:50]=1[C:62]([F:64])([F:65])[F:63]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(OC)cc3)csc2C(F)(F)F)c(F)c1
Agent: CCOC(=O)CCc1c(F)cc(O)cc1F
Agent: COc1ccc(-c2csc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Product: COc1ccc(-c2csc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 182 by coupling of [4-(4-methoxyphenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate and ethyl 3-(2,6-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis of ethyl 3-(3,5-difluoro-4-((4-(4-methoxyphenyl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)phenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.0 Hz, 2H), 7.38 (s, 1H), 6.95 (d, J=6.5 Hz, 2H), 6.72 (d, J=7.0 Hz, 1H), 5.08 (s, 2H), 3.85 (s, 3H), 2.90 (t, J=5.5 Hz, 2H), 2.66 (t, J=6.8 Hz, 2H). LCMS (ESI, M/Z) for C22H17F5O4S: 473.1 (MH+).