Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([NH:13][C:14]2[C:15]([CH3:24])=[N:16][CH:17]=[C:18]([CH:23]=2)[C:19]([O:21]C)=[O:20])=[O:12])[CH:7]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[CH3:24][C:15]1[C:14]([NH:13][C:11]([C:10]2[CH:9]=[N:8][N:6]3[CH:7]=[C:2]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)[CH:3]=[CH:4][C:5]=23)=[O:12])=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=1
Reactant: COC(=O)c1cnc(C)c(NC(=O)c2cnn3cc(Br)ccc23)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: Cc1ncc(C(=O)O)cc1NC(=O)c1cnn2cc(-c3cnn(C)c3)ccc12
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Methyl 5-(6-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-6-methylnicotinate (step 1) (7 g, 17.99 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.49 g, 21.58 mmol) and cesium carbonate (23.44 g, 71.9 mmol) were stirred in 1,2-dimethoxyethane (60 ml) and water (25.00 ml). The mixture was degassed thoroughly refilling with nitrogen. PdCl2(dppf).CH2Cl2 adduct (0.350 g, 0.429 mmol) was added and the mixture was degassed thoroughly refilling with nitrogen, The mixture was stirred at 100° C. for 7 hrs and then cooled to 50° C. and filtered through glass-fiber paper. The filtrate was acidified to pH 5 by the addition of 2M HCl and filtered. The foam residue was dissolved in DCM/MeOH (1:1) and azeotroped with toluene (×2). The resulting solid was dried in a vacuum oven to afford the title compound;
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1>C1COCC1>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]1=[O:9]
Reactant: O=C1CCCCCCC1
Reactant: Clc1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CCCCCCC1Cc1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Cyclooctanone Compound 1a (2.5 g, 19.8 mmol) in THF (5 mL) was added dropwise to a solution of LiHMDS (23.8 mL, 23.8 mmol) in anhydrous THF (50 mL) at −78° C. under a N2 atmosphere. The mixture was stirred at −78° C. for 60 mins, then 1-bromomethyl-3-chloro-benzene Compound 3a (4.1 g, 19.9 mmol) in anhydrous THF (10 mL) was added dropwise. The mixture was stirred for 5 hrs, while warming to r.t. The reaction was quenched with water (5 mL) and the organic layer was diluted with EtOAc (100 mL), then washed with water and brine. The organic layer was separated and dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to yield a crude oil which was purified by flash chromatography using 3% EtOAc in hexane to afford 2-(3-chloro-benzyl)-cyclooctanone Compound 3b (4.12 g, 82.6%).
Reaction SMILES: [CH3:1][C:2]1([OH:6])[CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.[C:13](Cl)([Cl:15])=[O:14]>C1C=CC=CC=1>[Cl:15][C:13]([O:6][C:2]1([CH3:1])[CH2:5][CH2:4][CH2:3]1)=[O:14]
Reactant: CC1(O)CCC1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(OC(=O)Cl)CCC1
Reaction time: 0.5 h

Procedure:
A solution of 0.55 gm. (6.5 mM) of 1-methylcyclobutanol, and 0.44 ml. of pyridine in 10 ml. of benzene is added to a solution of phosgene in 10 ml. of benzene at 0°C. over a 30 minute period. The reaction is allowed to stir for 30 minutes and then filtered to remove pyridine hydrochloride formed during the reaction. Excess phosgene is removed by evaporation at reduced pressure and the volume of the benzene solution is reduced to 4-5 ml; the benzene solution of 1-methylcyclobutylchloroformate is employed in the following reaction.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O-:11])=[O:10])=[C:7]([OH:14])[CH:6]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28]O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[C:30]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][O:14][C:7]2[CH:6]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:13]=[CH:12][C:8]=2[C:9]([O:11][CH3:30])=[O:10])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C([O-])c1ccc(OCCF)cc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCF)cc1OCC1CCCN(C(=O)OC(C)(C)C)C1
Yield: 120.6 %

Procedure:
Using a procedure similar to that of Example 26-B, 4-(2-fluoroethoxy)-2-hydroxybenzoate (2.6 g, 12.8 mmol), 1-tert-butoxycarbonylpiperidin-3-ylmethanol (2.76 g, 12.8 mmol), and triphenylphosphine (4.02 g, 15.4 mmol) in THF (50 mL) is treated with diethyl azodicarboxylate (2.59 g, 12.8 mmol) in THF to afford methyl 2-(1-tert-butoxycarbonyl-piperidin-3-ylmethoxy)-4-(2-fluoroethoxy)benzoate (6.35 g) which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.F[P-](F)(F)(F)(F)F.[N:34]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=N1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>CN(C=O)C.CCOC(C)=O>[NH2:34][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[NH:36][C:21]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[O:15])=[CH:25][CH:24]=1)=[O:22]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc21
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(C(=O)Nc4ccccc4N)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.2 %

Procedure:
To a solution of 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)benzoic acid 4 (151 mg) in DMF 2 mL was added BOP (0.266 g), triethylamine (0.238 mL, 0.60 mmol) and phenylenediamine (0.093 g, 0.86 mmol). The reaction mixture was stirred 1 h at RT and diluted in EtOAc (25 mL), washed with NaH2PO4 (1M, 2×25 mL), brine (1M, 2×25 mL), NaHCO3 (1M, 2×25 mL), brine (1M, 2×25 mL), dried over Na2SO4, filtered and concentrated to give an oil that was purified using silica gel chromatography with 40% [v/v] EtOAc in cyclohexane to give N-(4-(2-aminophenylcarbamoyl)phenyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamide EHT 1800 (8 mg, 4% yield) as a white solid.
Reaction SMILES: C(C1C=CC2C(C)(C)CCC(C)(C)C=2C=1)=O.O[CH:18]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1.S(Cl)([Cl:43])=O>>[Cl:43][CH:18]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1
Reactant: CCOP(=O)(OCC)C(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=S(Cl)Cl
Agent: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Product: CCOP(=O)(OCC)C(Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 88 %

Procedure:
216 g (1 mole) of 2-formyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene were converted to 251 g (71%) of diethyl 1-hydroxy-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-methylphosphonate of melting point 93°-95° C., and 188.4 g (88%) of the title compound were obtained from 203 g (0.57 mole) of the last-mentioned compound and 287 ml of thionyl chloride. Since the material decomposes during distillation, the working up procedure was modified as follows. The crude product obtained after removal of the thionyl chloride was dissolved in toluene, and the solution stirred with 5 g of potassium carbonate for 20 minutes. The solid was filtered off, the solvent was removed and the solidified mass was comminuted in a mortar. The material thus obtained (m.p. 65°-66° C.) was about 85% pure according to the H-NMR spectrum.
Reaction SMILES: [Si]([C:5]1[CH:6]=[C:7]([Si:11]([CH3:16])([CH3:15])[O:12]C#C)[CH:8]=[CH:9][CH:10]=1)(C)(C)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1.[CH:28]#[CH:29]>C1C=CC=CC=1>[C:22]([C:17]1[CH:27]=[C:16]([Si:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:28]#[CH:29])[CH:6]=2)([CH3:15])[O:12][Si:11]([CH3:16])([CH3:15])[CH3:7])[CH:20]=[CH:19][CH:18]=1)#[CH:21]
Reactant: C#CO[Si](C)(C)c1cccc([Si](C)(C)C)c1
Reactant: C#C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C#Cc1cccc([Si](C)(O[Si](C)(C)C)c2cccc(C#C)c2)c1
Yield: 88 %

Procedure:
The above-described ethynyl silanol (5.0 g, 0.028 mol) from Example 4 was dissolved in dry benzene (40 mL) and a trace of p-toluene sulfonic acid was added. The reaction was refluxed for 4 hours. Gas chromatographic analysis of the reaction mixture showed the condensation to be complete. The solution was washed well with water, dried over sodium sulfate, concentrated, and distilled at reduced pressure to give a pale yellow liquid (b.p. 125° C./0.01 torr, 4.2 g, 88% yield). Differential scanning calorimetric analysis of this liquid showed the characteristic exotherm of acetylene polymerization at 180° to 250° C. The heat of reaction was 70 calories/gram. The liquid had the following spectral characteristics:
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([F:25])[CH:18]=2)[CH:10]=1)[CH3:2].[NH2:26][NH2:27].CCN(C(C)C)C(C)C>CC#N>[CH2:1]([C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([C:17]2[CH:24]=[C:23]3[C:20]([C:21]([NH2:22])=[N:26][NH:27]3)=[C:19]([F:25])[CH:18]=2)[CH:10]=1)[CH3:2]
Reactant: NN
Reactant: CC[C@@H]1COCCN1c1cc(-c2ccc(C#N)c(F)c2)nc(NC)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1COCCN1c1cc(-c2cc(F)c3c(N)n[nH]c3c2)nc(NC)n1
Yield: 29.3 %

Procedure:
4-[6-[(3R)-3-Ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluorobenzonitrile (0.453 g, 1.261 mmol) was taken up in CH3CN (5 mL) followed by the addition of hydrazine (0.158 mL, 5.04 mmol) and Hunig's base (1.76 mL, 10.1 mmol) in a 20 mL microwave vial. The reaction was irradiated at 150° C. for 1 hour. The reaction mixture was concentrated and purified by reverse phase HPLC (8-28% CH3CN/H2O, 0.1% TFA). Fractions were combined and diluted with EtOAc. The organics were washed with saturated NaHCO3 solution (2×) that was back extracted with EtOAc. The organics were combined and dried over Na2SO4. The product was taken up in 2 mL H2O and lyophilized to afford the title compound (137 mg) as a white fluffy powder. LC-MS (ES) m/z=372 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (t, 3H), 1.60-1.81 (m, 2H), 2.82 (d, J=4.0 Hz, 3H), 3.05-3.16 (m, 1H), 3.43 (d, J=2.53 Hz, 1H), 3.51 (dd, J=11.5, 2.9 Hz, 1H), 3.83 (d, J=11.4 Hz, 1H), 3.89 (dd, J=11.1, 3.0 Hz, 1H), 4.03 (d, J=7.1 Hz, 1H), 4.16-4.28 (m, 1H), 4.30-4.43 (m, 1H), 5.26 (s, 2H), 6.58 (bs, 2H), 7.36 (d, J=12.4 Hz, 1H), 7.84 (bs, 1H), 11.89 (s, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:33])([F:32])[C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[CH2:11][N:12]1[CH2:16][C@H:15]2[C@H:17]([NH:20][C:21](=[O:28])[C@H:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH2:23])[CH2:18][CH2:19][C@H:14]2[CH2:13]1.CN[C@H:36](C(N[C@@H]1[C@H]2[C@H](CN(CC3C=CC=C(C(F)(F)F)C=3)C2)CC1)=O)[CH2:37]C(C)C>>[CH:1]1([S:2]([NH:23][C@H:22]([C:21]([NH:20][C@H:17]2[C@H:15]3[C@H:14]([CH2:13][N:12]([CH2:11][C:10]4[CH:29]=[CH:30][CH:31]=[C:8]([C:7]([F:32])([F:6])[F:33])[CH:9]=4)[CH2:16]3)[CH2:19][CH2:18]2)=[O:28])[CH2:24][CH:25]([CH3:26])[CH3:27])(=[O:4])=[O:3])[CH2:37][CH2:36]1
Reactant: CS(=O)(=O)Cl
Reactant: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Product: CC(C)C[C@H](NS(=O)(=O)C1CC1)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
The title compound was prepared by substituting cyclopropanesulfonyl chloride for methanesulfonyl chloride and N1-{(3aS,4R,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide from Example 170 Step B for N2-methyl-N1-{(3aS,4S,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide in the procedure described in Example 167: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.34 (d, J=9.4, 1H), 9.03 (d, J=7.2, 1H), 7.76 (s, 1H), 7.60 (d, J=10.5, 2H), 7.44 (dd, J=6.1, 13.8, 1H), 4.45 (dd, J=6.4, 11.7, 2H), 3.57 (d, J=13.5, 1H), 3.49 (d, J=13.5, 1H), 2.84 (dd, J=2.4, 9.1, 1H), 2.80-2.73 (m, 1H), 2.61-2.50 (m, 2H), 2.38 (dd, J=7.0, 8.9, 1H), 2.34 (dd, J=2.5, 9.0, 1H), 2.28-2.23 (m, 1H), 2.18 (td, J=5.8, 11.9, 1H), 2.04 (dt, J=6.9, 20.3, 1H), 1.91 (ddd, J=4.1, 7.2, 14.3, 2H), 1.77 (ddd, J=5.3, 8.7, 13.8, 1H), 1.73-1.65 (m, 1H), 1.44 (ddd, J=6.1, 12.3, 18.6, 1H), 1.33 (td, J=4.7, 11.0, 1H), 1.22-1.16 (m, 1H), 0.91 (ddd, J=4.5, 8.5, 11.2, 1H), 0.88-0.85 (m, 1H), 0.84 (d, J=6.7, 3H), 0.82 (d, J=6.6, 3H); MS (ESI+) m/z 502 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]2[C:11]=1[C:12]([CH3:22])([CH3:21])[CH2:13][CH2:14][S:15]2>C(Cl)Cl>[C:5]([C:19]1[C:10]([Cl:9])=[C:11]2[C:16](=[C:17]([Cl:20])[CH:18]=1)[S:15][CH2:14][CH2:13][C:12]2([CH3:22])[CH3:21])(=[O:7])[CH3:6]
Reactant: CC1(C)CCSc2c(Cl)ccc(Cl)c21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2c(c1Cl)C(C)(C)CCS2
Temperature: 0 °C
Yield: 55.7 %

Procedure:
1.26 Grams (9.45 mmol) of anhydrous aluminum chloride was suspended in 10 ml of methylene chloride, and a solution of 0.74 g (9.45 mmol) of acetyl chloride in 5 ml of methylene chloride was dropwise added with cooling with ice. The mixture was stirred until the reaction mixture was homogeneous, then, a solution of 1.95 g (7.88 mmol) of 5,8-dichloro-4,4-dimethylthiochroman in 5 ml of methylene chloride was added, and the mixture was allowed to react at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was poured into ice water and extracted with methylene chloride. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The methylene chloride was distilled off under reduced pressure, and the resultant oily substance was purified by silica gel column chromatography to give 1.27 g (yield 56%) of 6-acetyl-5,8-dichloro-4,4-dimethylthiochroman.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][S:4]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=1)=[O:5].[CH3:15][O:16][C:17]([NH:19][C:20](=NC(OC)=O)SC)=[O:18]>CO.C(O)(=O)C>[CH3:1][CH:2]([CH3:14])[CH2:3][S:4]([C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:20]([NH:19][C:17](=[O:18])[O:16][CH3:15])=[N:13][C:8]=2[CH:7]=1)=[O:5]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: CC(C)CS(=O)c1ccc(N)c(N)c1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(S(=O)CC(C)C)ccc2[nH]1
Yield: 70 %

Procedure:
To 3.09 g (14.5 mMol) of 4-(2-methylpropyl)sulfinyl-1,2-diaminobenzene in 35 ml methanol and 0.84 ml acetic acid is added 3.11 g (16 mMol) 1,3-bis(methoxycarbonyl)-S-methyl isothiourea, prepared as described in Example 1A(5), and the resulting solution heated to reflux for 3 hours. The solvent is removed in vacuo, the solid digested with water and filtered and washed with ether. The resulting orange solid is recrystallized from 35 ml ethanol to yield 3.0 g of the title compound, m.p. 198°-201°, yield, 70%.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12].[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH2:28].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH:28][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:8]([O:7][CH3:6])[CH:9]=1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1OC
Reactant: CC1CCCCC1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1ccc(C(=O)NC2CCCCC2C)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
To a mixture of 3 ml of THF and 0.3 g of 3-methoxy-4-(2-propynyloxy)benzoyl chloride were added dropwise 0.19 g of 2-methylcyclohexylamine and 0.16 g of triethylamine in order under ice cooling. The mixture obtained was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture and it was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.36 g of N-(2-methylcyclohexyl)-3-methoxy 4-(2-propynyloxy)benzamide (hereinafter, described as the compound 2 of the present invention) represented by the formula:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.N1[CH:30]=[CH:29]C=CC=1.[CH:31]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(Cl)Cl>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:37]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)(=[O:39])=[O:38])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1.[CH2:29]([O:38][CH2:20][CH3:23])[CH3:30]
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: c1ccncc1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)C3CCCCC3)c2F)c(-c2ccnc(N)n2)s1
Product: CCOCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 463.6 %

Procedure:
To a solution of 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.291 mmol) in DCM (2 ml), pyridine (0.4 mL, 4.95 mmol) was added followed by cyclohexylsulfonyl chloride (0.042 mL, 0.291 mmol). The solution was allowed to stir at rt for 24 h at rt. The solvent was removed and the concentrated residue was allowed to sit at rt overnight. The residue was then evaporated onto silica gel and chromatographed (1:9 MeOH:EtOAc in DCM). The title compound was obtained after trituration in diethyl ether (50 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.65 (s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.33 (t, J=6.4 Hz, 1H), 7.26 (t, J=7.9 Hz, 1H), 6.72 (s, 2H), 6.01 (d, J=5.1 Hz, 1H), 2.79-2.92 (m, 1H), 1.92-2.05 (m, 2H), 1.68 (d, J=12.6 Hz, 2H), 1.47-1.57 (m, 1H), 1.38 (s, 9H), 1.22-1.36 (m, 2H), 1.07-1.24 (m, 3H). MS (ESI): 490.2 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[C:9](Cl)(=[O:13])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:10][C:9]([O:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1)=[O:13])[CH3:12]
Reactant: O=C1C=CC(O)OC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1C=CC(=O)CO1
Temperature: 0 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
12 g of 6-hydroxy-2H-pyran-3(6H)-one was dissolved in 100 ml of methylene chloride, and the solution was cooled to 0° C. Then, 11.4 g of ethyl chlorocarbonate was added, and a solution comprising 10.6 g of triethylamine and 20 ml of methylene chloride was dropwise added thereto. The mixture was stirred for 3 hours, and the reaction mixture was poured into ice water and extracted with methylene chloride. The solvent was distilled off under reduced pressure, and the residue was subjected to distillation under reduced pressure to obtain 12.3 g (yield: 63%) of the above-identified compound.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[NH:9])[CH:3]=[CH2:4].[Na].[N:16](=[C:18]([C:24]#[N:25])[C:19](OCC)=[O:20])[OH:17].O>CO.C(O)(=O)C>[CH2:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]1[NH:10][C:19](=[O:20])[C:18]([N:16]=[O:17])=[C:24]([NH2:25])[N:9]=1)[CH:3]=[CH2:4]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: C=CCOc1ccccc1C(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: C=CCOc1ccccc1-c1nc(N)c(N=O)c(=O)[nH]1
Yield: 55.9 %

Procedure:
2-Allyloxybenzamidine hydrochloride (10.2 g.) was added to a solution of sodium (4.6 g.) in anhydrous methanol (200 ml.) with stirring, followed by ethyl α-oximinocyanoacetate (7.6 g.), and the mixture was stirred under reflux for 6 hours. The hot mixture was poured into water (500 ml.) and acidified with glacial acetic acid. The blue solid was filtered off, washed with water and recrystallised from 50% aqueous acetic acid to give 2-(2-allyloxyphenyl)-4-amino-5-nitrosopyrimid-6-one (7.3 g.), m.p. 217°-220° C.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:56])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@H:26]2[C@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=3[F:38])[C@:29]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[F:48])([C:39]#[N:40])[C@H:28]([CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])[NH:27]2)=[O:25])=[C:19]([O:54][CH3:55])[CH:18]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>>[ClH:37].[CH3:6][NH:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:56])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@H:26]2[C@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=3[F:38])[C@:29]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[F:48])([C:39]#[N:40])[C@H:28]([CH2:49][C:50]([CH3:51])([CH3:53])[CH3:52])[NH:27]2)=[O:25])=[C:19]([O:54][CH3:55])[CH:18]=1)=[O:11]
Reactant: COc1cc(C(=O)OCCOC(=O)CN(C)C(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Product: CNCC(=O)OCCOC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Product: Cl

Procedure:
4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-[2-(tert-butoxycarbonyl-methyl-amino)-acetoxy]-ethyl ester (Example 31) was treated with trifluoroacetic acid to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(2-methylamino-acetoxy)-ethyl ester, hydrochloride. MS (ES+) m/z calcd. for C36H39Cl2F2N4O6: [(M+H)+]: 731. found: 731.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)(=O)C>[C:12]1([CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCOCCOCCCc1ccccc1
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(CCCOCCOCCCNCc2ccccc2)cc1
Reaction time: 4.5 h
Yield: 78.8 %

Procedure:
[3-[2-(3-Bromopropoxy)ethoxy]propyl]benzene (3.01 g) was added dropwise over 5 min to benzylamine (5.35 g) at 120° under nitrogen. The solution was stirred at 130° for 4.5 h, cooled, diluted with ethyl acetate (200 ml) and washed with 2N hydrochloric acid (150 ml). The aqueous phase was re-extracted with ethyl acetate (2×100 ml) and the combined organic phases washed with 8% sodium bicarbonate solution (200 ml), dried and evaporated in vacuo to give the title compound (2.58 g) as an oil. T.l.c. (System E 40:10:1) Rf 0.49