Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][N:33]3COCC[Si](C)(C)C)=[CH:29][CH:28]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1.C(OCC)(=O)C>O1CCCC1>[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][NH:33]3)=[CH:29][CH:28]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3cc(Cl)cc(Cl)c3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3cc(Cl)cc(Cl)c3)ccc12
Temperature: 65 °C

Procedure:
11.2 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1 g of N-[6-(3,5-dichlorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 20 cm3 of tetrahydrofuran, the reaction medium is then heated at about 65° C. for 18 hours and the heating is stopped to add 75 cm3 of ethyl acetate. The organic phase is washed with 2×50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 50° C.), 290 mg of N-[6-(3,5-dichlorophenyl)-1H-indazol-3-yl]butanamide are obtained in the form of a white product.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]1)=[CH:13][C:12]([C:31]1[CH:36]=[C:35]([F:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=1)=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].O.Cl>C1COCC1>[NH2:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:36]=[C:35]([F:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:18][CH2:19]1
Reactant: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
To a suspension of tert-butyl (trans-4-((3-butyryl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)quinolin-4-yl)amino)cyclohexyl)carbamate (36 mg, 0.065 mmol) in THF (3 mL) was added water (2 mL) and 6N aqueous HCl (2 mL). The resultant solution was heated at 65° C. for 4 h. The reaction mixture was cooled and concentrated. The resultant residue was triturated with diethyl ether. The residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired product (21.1 mg, 71%) as a yellow solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.15 (s, 1H), 8.47 (s, 1H), 8.28 (dd, J=8.7, 1.8 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.51 (d, J=11.4 Hz, 1H), 4.55 (br s, 1H), 3.13 (t, J=7.2 Hz, 2H), 2.53-2.49 (m, 2H), 2.26 (d, J=12.1 Hz, 2H), 1.94-1.74 (m, 4H), 1.68-1.62 (m, 2H), 1.06 (t, J=7.4 Hz, 3H). ESI MS m/z 456 [C25H27ClFN3O2+H]+; HPLC>99% (AUC), tR=10.83 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc3sc(-c4nc(NCCN5C(=O)NC(=O)C5(C)C)ncc4Br)cc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3cc(OCCN4CCNCC4)ccc3s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
tert-butyl 4-(2-(2-(5-bromo-2-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)ethylamino)-pyrimidin-4-yl)benzo[b]thiophen-5-yloxy)ethyl)piperazine-1-carboxylate (0.23 g, 3.3 mmol) dissolved in dichloromethane (3 mL) was treated with trifluoroacetic acid (3 mL) and the mixture stirred at room temperature overnight. The volatiles were removed in vacuo and the residue dissolved in dichloromethane. The organic solution was washed with water, saturated sodium bicarbonate and brine. The solution was dried with sodium sulfate and purified by column chromatography using a gradient of 8% to 20% methanol in dichloromethane to give an off-white solid (0.143 g). MS (M+H)+ 588/590.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([N:18]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]2)[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[CH:15]1([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19]2)[CH2:17][CH2:16]1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NC1CCN(C2CC2)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(NC2CCN(C3CC3)CC2)c([N+](=O)[O-])c1

Procedure:
To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.26 g) and 1-cyclopropylpiperidin-4-amine (0.802 g) in tetrahydrofuran (20 mL) was added N,N-diisopropylethylamine (2.22 g) and 4-dimethylaminopyridine (35 mg). The mixture was heated at reflux for 18 hours and upon cooling was diluted with ethyl acetate (200 mL) and aqueous NaHCO3. The crude product was isolated by concentration of the organic layer and was purified on silica gel, which was eluted with 5% methanolic ammonia in methylene chloride to give the title compound.
Reaction SMILES: N[CH:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:3]1.[C:18]([O:22][C:23](NC(C1C=CC=CC=1)C#N)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([CH:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:3]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: C[C@H](c1ccccc1)N1CC(N)C2(CCC2)C1
Reactant: CC(C)(C)OC(=O)NC(C#N)c1ccccc1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC(C(=O)OC(C)(C)C)C2(CCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
To an ice-cooled solution of 2.9 g of 8-amino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane in 30 ml of tetrahydrofuran there was added 3.3 g of 2-(tertbutoxycarbonylamino)-2-phenylacetonitrile and the resulting mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure, and ethyl acetate was added to the resulting residue. The mixture was washed with a 1N sodium hydroxide aqueous solution three times and then dried. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography using 50 g of silica gel. The column was eluted with chloroform, chloroform containing methanol and 4.1 g of the titled compound was obtained from a eluate when the eluant was chloroform containing 1% (v/v) of methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[C:9]([NH:8][C:4]1[CH:5]=[CH:6][C:7]([S:13]([Cl:12])(=[O:15])=[O:14])=[C:2]([F:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1cccc(F)c1
Product: CC(=O)Nc1ccc(S(=O)(=O)Cl)c(F)c1
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of N-(3-fluorophenyl)acetamide (20.0, 0.13 mol) in chlorosulfonic acid (150 mL) was heated to 75° C. for 1 hr. The solution was allowed to cool to room temperature and was poured over ice. The resulting slurry was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to yield 15.5 g (47%) of 4-acetylamino-2-fluorobenzenesulfonyl chloride as a paste. The crude material was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:11].CN(C)CCN(C)C.C([Li])CCC.CCCCCC.CN([CH:34]=[O:35])C.[Cl-].[NH4+]>CCOCC>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[CH:34]=[O:35]
Reactant: CN(C)C=O
Reactant: COc1cccc(C)c1OC
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1c(C)ccc(C=O)c1OC
Temperature: 0 °C
Yield: 53.8 %

Procedure:
2,3-Dimethoxytoluene (2 g, 13.1 mmol) was weighed in a flask and ether was added to the flask. N,N,N′,N′-tetramethylethylenediamine (422 mg, 3.6 mmol) was added to the solution. While stirring, the mixture was cooled down to 0° C. and n-Butyl lithium 1.6M in hexane (2.25 mL, 3.6 mmol) was added slowly over 20 minutes. The solution was stirred at 0° C. for 30 minutes after which the ice bath was removed. The solution became yellow during addition and after removal of the ice bath, a precipitate started forming. The reaction mixture was left stirring overnight at room temperature under nitrogen then cooled down again to 0° C. and DMF (1.23 mL, 15.9 mmol) was added. The homogeneous reaction mixture was stirred at this temperature for 1 hour. The solution was poured onto crushed ice and 15 mL ammonium chloride 1N. The phases were separated and the organic phase was washed with 4 portions of 1N ammonium chloride. The organics were dried over sodium sulphate, filtered and the filtrate was evaporated under vacuum. The crude product was purified on normal silica with DCM to yield 1.27 g (58%) of 14 which was used in the next stage.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([CH3:48])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[C:12]([C:22]([NH:24][C:25]2([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41]([O:43]CCCC)=[O:42])[CH:37]=[CH:38][C:31]=5[N:30]=4)[CH2:28][CH2:27][CH2:26]2)=[O:23])[CH:11]=3)=[N:6][CH:7]=1.C1COCC1.CO.[OH-].[Na+].[Na]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([CH3:48])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:14][CH:13]=[C:12]([C:22]([NH:24][C:25]2([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42])[CH:37]=[CH:38][C:31]=5[N:30]=4)[CH2:26][CH2:27][CH2:28]2)=[O:23])[CH:11]=3)=[N:6][CH:7]=1
Reactant: CCCCOC(=O)/C=C/c1ccc2nc(C3(NC(=O)c4ccc5c(C6CCCC6)c(-c6ncc(Br)cn6)n(C)c5c4)CCC3)n(C)c2c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Cn1c(C2(NC(=O)c3ccc4c(C5CCCC5)c(-c5ncc(Br)cn5)n(C)c4c3)CCC2)nc2ccc(/C=C/C(=O)O)cc21

Procedure:
In this process, hydrolysis of (E)-butyl 3-(2-(1-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido)cyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate was carried out in mixture of THF/MeOH and aq NaOH. Controlled acidification of the corresponding sodium salt with acetic acid is very critical to obtain easy-filtering crystalline product in high yield and purity.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:25][C:26]1[S:30][C:29]([CH2:31]Cl)=[CH:28][CH:27]=1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3SC(Cl)=CC=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:31][C:29]3[S:30][C:26]([Cl:25])=[CH:27][CH:28]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClCc1ccc(Cl)s1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc(Cl)s3)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3ccc(Cl)s3)c3c2CCNCC3)cc1
Yield: 38.3 %

Procedure:
The title compound (0.029 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 5-chloro-thiophen-2-ylmethyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(5-chloro-thiophen-2-ylmethyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C18H17Cl2N3S, 377.05; found, m/z 378.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.51 (m, 2H), 7.49-7.46 (m, 2H), 3.91 (d, J=3.8 Hz, 1H), 6.86 (d, J=3.8 Hz, 1H), 5.51 (s, 2H), 3.45-3.44 (m, 2H), 3.38-3.61 (m, 2H), 3.27-3.25 (m, 2H), 3.07-3.05 (m, 2H).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.C[O-].[Na+].[Cl:16][C:17]1[C:28]([NH:29][S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[CH:27][C:20]([NH:21][C:22](=O)[O:23]CC)=[C:19]([F:35])[CH:18]=1>CN(C)C=O>[Cl:16][C:17]1[C:28]([NH:29][S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[CH:27][C:20]([N:21]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:22]2=[O:23])=[C:19]([F:35])[CH:18]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCOC(=O)Nc1cc(NS(=O)(=O)CC)c(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 5 °C
Yield: 77 %

Procedure:
1.06 g (5.77 mmol) of ethyl 3-amino-4,4,4-trifluorocrotonate was dissolved in 6.2 ml of N,N-dimethylformamide and 0.82 g (14.4 mmol) of sodium methoxide was added thereto. The reaction mixture was cooled to not higher than 5° C. after 10 minutes, and 1.56 g (4.81 mmol) of ethyl 4-chloro-5-ethylsulfonylamino-2-fluorocarbanilate was added thereto. The resultant mixture was heated to 110° C. and reacted for 4 hours. After the reaction was completed, N,N-dimethylformamide was distilled off and the resultant product was dissolved in water. The thus-obtained solution was washed with diethyl ether 3 times and thereafter concentrated hydrochloric acid was added thereto to pH 2. The precipitated crystals were filtered out, washed with water and dried to obtain 1.54 g of the objective product (yield: 77%) in the form of light yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]([CH3:9])[NH:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18].O>C1COCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]([CH3:9])[NH:7][O:8][C:4]=2[C:3]=1[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: CC1NOc2cc(F)ccc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1NOc2c1ccc(F)c2C(=O)O
Reaction time: 1 h

Procedure:
A stirred solution of 6-fluoro-3-methyl-1,2(2H)-benzisoxazole (5.5 g, 0.037 mole) in THF (100 mL) was cooled in a dry ice-acetone bath, and 2.5 M n-butyllithium in hexanes (16 mL, 0.040 mole) was added dropwise. Upon completion of addition, the reaction mixture was stirred for one hour. The reaction mixture was then exposed to a CO2 atmosphere where it stirred for three hours. After this time, the reaction mixture was poured into water. The mixture was washed with ether, acidified with hydrochloric acid, and then extracted repeatedly with ether. The combine extracts were washed with water, dried with magnesium sulfate and concentrated yielding 4.5 grams of [6-fluoro-3-methyl-1,2(2H)-benzisoxazol-7-yl]carboxylic acid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[CH3:8].[Li]CCCC.C(NCC)C.[CH3:19][N:20]([CH:22]=O)[CH3:21]>C1COCC1>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[C:2]([CH3:8])[CH:3]=1
Reactant: Cc1ccnc(C)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCNCC
Solvent: C1CCOC1
Product: Cc1cc(C=CN(C)C)ccn1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
11.05 g 2,4-Lutidine (0.1 mol) were dissolved in 50 ml THF. The solution was cooled and stirred, maintaining the temperature at between −70 to −50° C. 81.25 ml nBuLi (0.13 mol) was added over 0.25 hour. The dark red solution was stirred for a further 0.5 hour, then 15.14 ml diethylamine (0.145 mol) was added in one portion producing an orange suspension. After a 0.5 hour, 15.5 ml DMF (0.2 mol) was added. The brown-red solution was stirred for 1 hour then quenched with 50 ml 50% saturated aqueous ammonium chloride solution. Upon warming to ambient temperature, the reaction mixture was extracted with tert. butyl methyl ether (TBME) (3×100 ml), and the combined organic phases were washed with 50 ml H2O, dried over Na2SO4, filtered and concentrated under reduced pressure (45° C./450-20 mbar) providing an orange-red oil (14.8 g, 91%) which was sufficiently pure (Gas Liquid Chromatography (GLC) 98 area %) to be used directly in the next step.
Reaction SMILES: O.[OH-].[Li+].[NH2:4][CH2:5][CH2:6][CH2:7][P:8]([CH:13]([O:18][CH2:19][CH2:20][CH3:21])[O:14][CH2:15][CH2:16][CH3:17])(=[O:12])[O:9]CC>O.C(O)C>[NH2:4][CH2:5][CH2:6][CH2:7][P:8]([CH:13]([O:18][CH2:19][CH2:20][CH3:21])[O:14][CH2:15][CH2:16][CH3:17])(=[O:9])[OH:12]
Reactant: CCCOC(OCCC)P(=O)(CCCN)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCOC(OCCC)P(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a stirred solution of 0.05 g of lithium hydroxide monohydrate in 7.7 ml of water, is added a solution of 4.37 g of ethyl 3-aminopropyl(di-n-propyloxymethyl)phosphinate in 16.2 ml of ethanol. A slight exothermic reaction ensues and the reaction mixture becomes cloudy. A further 2 ml of water are added and the clear solution stirred at room temperature for 5 days. After this time the mixture is concentrated in vacuo at 55° and the residue redissolved in water and extracted with 3×10 ml of dichloromethane. The aqueous layer is again evaporated to dryness and the residue dissolved in 20 ml of water and treated with 0.51 ml of 85% phosphoric acid. After stirring overnight, the solid is removed by filtration. Evaporation of the filtrate and crystallisation of the residue from ethanol/ether affords 3-aminopropyl(di-n-propyloxymethyl)phosphinic acid, m.p. 223°-225°, as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[N:22]=[C:23](C5CCN(C(OC(C)(C)C)=O)CC5)[NH:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C([CH:43]1[CH2:46][N:45]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:44]1)=O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[NH:22][C:23]([CH:43]5[CH2:44][N:45]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:46]5)=[N:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CN(C(=O)OC(C)(C)C)C2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 182.3, except tert-butyl 3-formylazetidine-1-carboxylate was used in place of tert-butyl 4-formylpiperidine-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5](Cl)=[N:6][CH:7]=1.BrC1C=N[CH:15]=[C:16]([O:18]C)C=1.[O-]CC.[Na+].C(O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([O:18][CH2:16][CH3:15])=[N:6][CH:7]=1
Reactant: COc1cncc(Br)c1
Reactant: COc1cc(Br)cnc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ncc(Br)cc1OC

Procedure:
As shown in step 5-i of Scheme 5, 5-bromo-2-chloro-3-methoxypyridine (1.0 g, 4.5 mmol, prepared in the same manner as Compound 1003 in Example 2 starting with 3-bromo-5-methoxypyridine) was treated with a sodium ethoxide/ethanol solution (5.05 mL, 21% w/v, 13.5 mmol) and the reaction mixture microwave irradiated at 100° C. for 20 minutes. Water was added and the ethanol evaporated under reduced pressure. The resulting aqueous solution was extracted with DCM and ether, followed by drying the combined extracts over MgSO4. After filtration, removal of the volatiles under reduced pressure provided 5-bromo-2-ethoxy-3-methoxypyridine (Compound 1016), 0.72 g, 69% yield): ESMS (M+H) 232.32/234.23. As shown in step 5-ii of Scheme 5, Compound 1017 (ESMS (M+H) 218.32/220.23) was prepared in the same manner as Compound 1016, using sodium methoxide in methanol instead of sodium ethoxide in ethanol.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:31])[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C@H:12]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([OH:40])[CH:34]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:41][O:42][CH2:43][CH2:44][O:45][CH2:46]Cl.O>CN(C)C=O>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:31])[C:17]2[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C@H:12]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([O:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH3:46])[CH:34]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 18 mg) was added by small portions to an ice-cooled solution of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine (0.20 g) in N,N-dimethylformamide (2 ml) below 5° C. under nitrogen atmosphere. After the mixture was stirred for 5 minutes, (2-methoxyethoxy)methyl chloride (0.064 ml) was added to the mixture. The whole was stirred at room temperature for 2.5 hours, and thereto water was added. The whole was extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using mixed solvents of hexane and ethyl acetate (7:3). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]piperazine (0.21 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=4)[N:14]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:23][C:27]([CH:24]5[CH2:26][CH2:25]5)=[O:28])[CH:19]=4)[N:14]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C1CC1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CO2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)C4CC4)ccc3n1)CO2

Procedure:
The title compound was prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine (Example 173) (154 mg, 0.5 mmol) and commercially available cyclopropanecarboxylic acid (40 ul, 0.5 mmol) in accordance with the general method 14 described in example 119 and was obtained as an off-white solid (68 mg, 36%); MS: m/e=376.3 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:12]=[C:11](C(Cl)(Cl)Cl)[O:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:17]>CCOCC>[NH2:17][C:11]1[O:10][N:9]=[C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: N
Reactant: ClC(Cl)(Cl)c1nc(Cc2ccccc2)no1
Solvent: CCOCC
Product: Nc1nc(Cc2ccccc2)no1

Procedure:
A mixture of 60 g. (0.22 moles) of 3-(phenylmethyl)-5-trichloromethyl-1,2,4-oxadiazole and 50 ml. of ether are added dropwise with stirring into 100 ml. of liquid ammonia and stirred for an additional hour. The ammonia and ether are evaporated, the residue is treated with a little water and filtered under suction. 33.3 g. of 5-amino-3-(phenylmethyl)-1,2,4-oxadiazole are obtained, m.p. 142°-145°. After recrystallization from ethanol the compound melts at 145°-146°.