Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][C@H:9]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:7]2([CH3:8])[C@H:6]1[N:25]([CH3:32])[C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].C1(C)C=CC=CC=1>ClC1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[CH2:10][C@H:9]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:7]2([CH3:8])[C@H:6]1[N:25]([CH3:32])[C:26](=[O:31])[C:27]([F:29])([F:28])[F:30])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH:17]=[CH:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1N(C)C(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: CC(=O)O[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1N(C)C(=O)C(F)(F)F
Yield: 81.2 %

Procedure:
A solution of 16α-acetyloxy-17β-(N-trifluoroacetyl-methylamino)-androst-4-en-3-one (1.88 g) and diphenylselenic anhydride (1.7 g) in chlorobenzene (39 ml) was heated under reflux for 1 h. The solution was cooled, toluene was added and the solution was filtered through a column (7.5 cm×2.5 cm) of silica gel (0.063-0.2 mm). Elution with toluene removed diphenylselenide. Elution with ether yielded a fraction which was evaporated to dryness to give 16α-acetyloxy-17β-(N-trifluoroacetyl-methylamino)-androsta-1,4-dien-3-one as a yellow gum (1.52 g). A solution of the product in ethanol (40 ml) and aqueous sodium hydroxide solution (3 ml; 4 N) was heated under reflux for 1.5 h.; the solution was concentrated and cooled, then water was added to precipitate an off-white solid, which was filtered off, washed with water and dried in vacuo to give 16α-hydroxy-17β-methylamino-androsta-1,4-dien-3-one (1 g). The product was dissolved in ethanol (20 ml), a solution of maleic acid (0.37 g) in ethanol (10 ml) was added and the resulting solution was treated with charcoal, filtered and evaporated to give a pale yellow gum (1.44 g). Crystallisation from acetone gave 16α-hydroxy-17β-methylamino-androsta-1,4-dien-3-one (Z)-2-butenedioate (1:1) (salt) as colourless prisms (0.88 g), m.p. 184°-191° C. (decomp.), [α]D +14.2° (c 0.88 in ETOH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8]N=1)=[O:5])[CH3:2].[H-].[Na+].FC(F)(F)C1C=CC(C(=[O:33])C)=CC=1.C(OC(=O)C(OCC)=O)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:5])[C:6](=[O:33])[CH2:10][C:9](=[O:8])[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)on1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)C(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Yield: 80 %

Procedure:
Preparation of 5-(4-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester (compound 42A) Sodium hydride (1.6 g, 63.7 mmol, 95%) was added to a solution of 1(4-trifluoromethyl-phenyl)-ethanone (10.0 g, 53.1 mmol) and oxalic acid diethyl ester (8.7 mL, 63.7 mmol) in 75 mL dry DMF at 0° C. The reaction was allowed to come to room temperature and then heated to 45° C. for 45 minutes. The reaction was then cooled, concentrated in vacuo, and the residue taken up in EtOAc. The organic layer was then washed with 2 M HCl (1×100 mL), dried (Na2SO4) and the solvent removed in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexane to 55% EtOAc/hexane) gave the intermediate 2,4-dioxo-4-(4-trifluoromethyl-phenyl)-butyric acid ethyl ester (12.2 g, 80%) which was then taken up in EtOH and refluxed in the presence of hydroxyl amine hydrochloride (10.2 g, 132.3 mmol) for 3H. The reaction was then cooled, diluted with EtOAc, washed with dilute NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo. Recrystallization from EtOAc/hexane gave 5.2 g of the title compound. MS m/z 286 (M+1). Step 2. Preparation of [5-(4-Trifluoromethyl-phenyl)-isoxazol-3-yl]-methanol (compound 42B) The title compound was prepared in a manner analogous to Example 40B using 42A. MS m/z 244 (M+1). Step 3. Preparation of 3-chloromethyl-5-(4-trifluoromethyl-phenyl)-isoxazole (compound 42C) The title compound was prepared in a manner analogous to Example 3B using 42B. MS m/z 262 (M+1). Step 4. Preparation of {2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 42 The title compound was prepared in a manner analogous to Example 1F using 42C and 2C. MS m/z 438 (M+1). Step 5. Preparation of {2Methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-acetic acid (compound 42) The title compound was prepared in a manner analogous to Example 1 using 42D. IR cm−1:1746, 1326; 400 MHz 1H NMR (DMSO-d6) δ 12.97 (br(s), 1H), 8.02 (d, 2H, J=8.0 Hz), 7.83 (d, 2H, J=8.0 Hz), 7.20 (s, 1H), 7.15 (s, 2H), 6.71 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 4.14 (s, 2H), 2.08 (s, 3H); MS m/z 424 (M+1). Anal. Calc'd for C20H16F3NO4S C, 56.73; H, 3.81; N, 3.31 found: C, 56.59; H, 3.58; N, 3.22.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[C:7](#[N:10])[CH:8]=[CH2:9]>>[OH:6][C@H:3]1[CH2:4][CH2:5][N:1]([CH2:9][CH2:8][C:7]#[N:10])[CH2:2]1
Reactant: O[C@H]1CCNC1
Reactant: C=CC#N
Product: N#CCCN1CC[C@H](O)C1

Procedure:
By the reaction in the same manner as in Starting Material Synthesis Example 1 using (S)-(+)-3-pyrrolidinol (12.3 g) and acrylonitrile (10.2 mL), (S)-3-(3-hydroxypyrrolidin-1-yl)propionitrile (53 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C@@H:6]1[O:11][C@@H:10]([CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9][CH2:8][CH2:7]1.[Na].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>CN(C)C=O>[Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C@@H:6]1[O:11][C@@H:10]([CH2:12][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[CH2:9][CH2:8][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3ccc(Cl)cc3Cl)O2)cc1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CN(C)C=O
Product: Clc1ccc(CO[C@H]2CCC[C@H](Cn3ccnc3)O2)c(Cl)c1

Procedure:
As in Example 1(b), 5 ml of a dimethylformamide solution containing 1.70 g of trans-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran were added to 15 ml of a dimethylformamide solution containing 5.73 mmoles of the sodium salt of imidazole and the mixture was allowed to react for 2 hours at 85° C., after which it was treated and purified as in Example 1(b), to give 1.2 g of the title compound as a colourless oil.
Reaction SMILES: CI.[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[C:19]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:43]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:25])=[O:26])=[C:19]([N:33]([CH3:43])[S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:35])=[O:36])[CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(NS(=O)(=O)c3ccccc3)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1NS(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MeI (45 μL, 0.72 mmol) was added to a mixture of N-{4-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide (0.189 g, 0.36 mmol) and K2CO3 (0.124, 0.90 mmol) in acetone (25 mL). The mixture was stirred at r.t. for 2 h, filtered and the solvent was removed. Purification by column chromatography (DCM/MeOH/heptane 4:1:15) gave N-{4-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-[methyl(phenylsulfonyl)-amino]phenyl}benzenesulfonamide as a colourless oil. Boc-deprotection was carried out by dissolving the compound in small amount of MeOH and adding HCl/ether. The solvent was removed and the residue was recrystrallized from MeOH/ether to give 62.7 mg of product M+1 501.3 Calcd 501.16.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:15]([NH:17][C:18]1([CH3:22])[CH2:21][CH2:20][CH2:19]1)=[O:16])[CH:6]=2.[Cl:27]CCl.ClN1C(=O)CCC1=O>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[Cl:27])=[CH:9][CH:8]=[C:7]([C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:15]([NH:17][C:18]1([CH3:22])[CH2:19][CH2:20][CH2:21]1)=[O:16])[CH:6]=2
Reactant: ClCCl
Reactant: Cc1ccc(C(=O)NC2(C)CCC2)cc1-c1ccc2cc(N)ncc2c1
Agent: O=C1CCC(=O)N1Cl
Product: Cc1ccc(C(=O)NC2(C)CCC2)cc1-c1ccc2c(Cl)c(N)ncc2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 31.4 %

Procedure:
A solution of 3-(3-aminoisoquinolin-7-yl)-4-methyl-N-(1-methylcyclobutyl)benzamide (50.0 mg; 0.145 mmol) in dichloromethane (3 mL; 46.80 mmol) was treated with N-chlorosuccinimide (27.9 mg; 0.209 mmol). The reaction mixture was stirred at room temperature for 7 hours. The crude reaction mixture was filtered through a plug of silica gel, which was rinsed with ethyl acetate. The filtrate was evaporated in vacuo and the resulting residue was purified via preparatory reverse-phase HPLC and lyophilized to yield 17.3 mg (32%) of the title compound. LCMS (ESI): RT (min)=5.078, M+H=380.2, method=E; 1H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.35 (s, 1H), 7.94 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.80 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 6.36 (s, 2H), 2.39-2.32 (m, 2H), 2.31 (s, 3H), 2.02-1.93 (m, 2H), 1.86-1.75 (m, 2H), 1.47 (s, 3H).
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[O:11]=[C:12]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:27][C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13]1.C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[CH:13]1[C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[O:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:12]1=[O:11])[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 101 %

Procedure:
To triethyl orthoformate (85 mL, 510 mmol) in dry dichloromethane (460 mL) under nitrogen at −10° C. was added dropwise BF3OEt2 (65 mL, 510 mmol). The solution was allowed to warm to 0° C. and was stirred for 10 minutes. The solution was cooled to −78° C. prior to the slow dropwise addition of tert-butyl 4-oxospiro[chromane-2,4′-piperidine]-1′-carboxylate (55 g, 170 mmol) in dichloromethane (25 mL). N-ethyl-N-isopropylpropan-2-amine (100 mL, 600 mmol) was added over a 30 minutes period, and the mixture was slowly warmed to 25° C. and was stirred at this temperature overnight. The reaction mixture was diluted with dichloromethane (500 mL) followed by saturated aqueous sodium bicarbonate solution (500 mL). The layers were separated, and the organic layer was washed with additional sodium bicarbonate (500 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-25% ethyl acetate in hexane) to provide tert-butyl 3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (72 g, 91%) as an orange oil. ESI-MS m/z calc. 419.5, found 420.3 (M+1)+; Retention time: 2.50 minutes (3 min run).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C1([Mg]Cl)C=CC=CC=1.[CH3:19][C:20]([CH3:24])([CH3:23])[CH:21]=[O:22]>C1COCC1>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:21]([OH:22])[C:20]([CH3:24])([CH3:23])[CH3:19])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CC(C)(C)C=O
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Under a nitrogen atmosphere, a solution of 1-iodo-2-nitrobenzene (3.0 g, 12 mmol) in anhydrous THF (30 mL) was cooled to minus 40° C., and then phenylmagnesium chloride (2 M in THF, 7.2 mL, 14.5 mmol) was added dropwise at a rate that the temperature would not exceed minus 35° C. After the mixture was stirred for 20 minutes at minus 40° C., trimethylacetaldehyde (1.85 mL, 16.8 mmol) was added dropwise and the mixture was stirred for another 30 minutes at minus 40° C. The mixture was gradually warmed up to room temperature, quenched with saturated ammonium chloride (60 mL), poured into water (60 mL), and extracted with ethyl acetate three times (60 mL each). The combined organic phase was dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield (RS)-1-(2-nitrophenyl)-2,2-dimethyl-1-propanol (1.82 g, 72%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, 1H, J=6.4 Hz, Ph-H), 7.76 (d, 1H, J=6.4 Hz, Ph-H), 7.61 (t, 1H, J=6.4 Hz, Ph-H), 7.39 (t, 1H, J=6.4 Hz, Ph-H), 5.39 (d, 1H, J=2.8 Hz, Ph-CH), 2.14 (d, 1H, J=3.2 Hz, OH), 0.89 (s, 9H, C(CH3)3).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])=[CH:48][CH:47]=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:29][C:4]1[CH:3]=[C:2]([NH:1][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:49]2[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=2)=[S:57])[CH:28]=[CH:27][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCC(N4CCCC4)CC3)ncn2)c(F)c1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCC(N4CCCC4)CC3)ncn2)c(F)c1
Reaction time: 0.08 h
Yield: 34 %

Procedure:
After suspending a crude product of 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (88.4 mg) in ethanol (3 ml), D-10-camphorsulfonic acid (51.3 mg) was added and the mixture was stirred for 5 minutes. A 0.2 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (1.3 ml) was added thereto and the mixture was stirred for 62 hours. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture for partition, and then the organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:9). Fractions containing the target compound were concentrated, and then diethyl ether (1 ml) and hexane (1.5 ml) were added to the resultant residue to produce a suspension. After filtering the solid, it was subjected to aeration drying to provide the title compound (44.7 mg, 34%) as pale pink powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]1=[O:28])[CH3:2].[CH3:31][S:32]([NH:35][CH2:36][C:37]#[CH:38])(=[O:34])=[O:33]>>[CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:38]#[C:37][CH2:36][NH:35][S:32]([CH3:31])(=[O:34])=[O:33])[CH:13]=2)[C:8]([OH:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]1=[O:28])[CH3:2]
Reactant: C#CCNS(C)(=O)=O
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(I)cc2C(F)(F)F
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(C#CCNS(C)(=O)=O)cc2C(F)(F)F

Procedure:
The title compound (270 mg) was prepared from (+)-1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-chlorophenyl)oxindole of Example 72(1) (347 mg, 0.628 mmol) and 1-methanesulfonylamino-2-propyne by the procedure similar to that described in Reference Example 21. The hydrochloride of the title compound was obtained by treating with 4 N HCl in dioxane followed by concentration to dryness.
Reaction SMILES: [BrH:1].Br.C[O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:8][CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][NH:10]1>Br>[BrH:1].[BrH:1].[OH:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:8][CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][NH:10]1
Reactant: COc1cc(CC2CNCCN2)ccc1C
Agent: Br
Product: Cc1ccc(CC2CNCCN2)cc1O
Yield: 151.4 %

Procedure:
A stirred solution of 2-(3-methoxy-4-methylbenzyl)piperazine dihydrobromide (240 mg) in 48% hydrobromic acid (8 ml) was heated under reflux for 48 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was triturated with ethyl acetate and the resulting precipitates were collected by filtration, and washed with ethyl acetate to give 2-(3-hydroxy-4-methylbenzyl)piperazine dihydrobromide (175 mg) as a powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:29][CH3:30])=[C:18]([O:21]CC5C=CC=CC=5)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][N:8]=2)[CH:3]=[CH:2]1.C([O-])=O.[NH4+].O>[Pd].CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:29][CH3:30])=[C:18]([OH:21])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][N:8]=2)[CH:3]=[CH:2]1
Reactant: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A solution of 4-(7-azaindol-5-yloxy)-6-benzyloxy-7-methoxyquinazoline (0.36 g, 0.873 mmol), ammonium formate (0.55 g, 8.73 mmol) and 10% palladium on carbon (0.05 g) in DMF (7 ml) containing water (0.3 ml) was stirred at ambient temperature for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was triturated under diethyl ether and the solid was filtered, washed with ether and dried under vacuum. The solid was triturated under water, filtered, washed with water and dried under vacuum over P2O5 to give 4-(7-azaindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.26 g, 85%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:15][P:16]([CH2:21][C:22]([OH:24])=O)([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].[Cl:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[C:35]3[CH:43]=[C:42]([NH2:44])[N:41]=[CH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[Cl:32].CC(N(C)C)=O>C1COCC1.O.ClCCl.CO>[Cl:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[C:35]3[CH:43]=[C:42]([NH:44][C:22](=[O:24])[CH2:21][P:16](=[O:17])([O:15][CH2:13][CH3:14])[O:18][CH2:19][CH3:20])[N:41]=[CH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: Nc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cn1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cn1)OCC
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
To a stirred mixture of CDI (1.98 g, 12.2 mmol) and dry THF (8 mL), at room temperature and under a nitrogen atmosphere, was added a solution of 2-(diethoxyphosphoryl)acetic acid (2.18 g, 11.1 mmol) in THF (6 mL). After addition the reaction mixture was stirred further at 40° C. (bath) for 15 min (whence evolution of gases ceased). A solution of compound 222 (1.70 g, 5.56 mmol) in a mixed solvents of dry THF (6 mL) and DMA (7 mL) was added and stirred further at 40° C. The reaction was monitored by TLC (dichloromethane-MeOH=15:1). After stirred overnight (17 h), the reaction mixture was poured into water (300 mL) and stirred with petroleum ether (400 mL) at room temperature for 20 min. Petroleum ether layer was decanted. It was repeated once more with petroleum ether (400 mL). The solid was collected by suction filtration; washed with water (5×30 mL) and dried to give diethyl 2-(4-(3,4-dichlorophenylamino)pyrido[3,4-d]pyrimidin-6-ylamino)-2-oxoethylphosphonate (231) (2.56 g, 95%); mp 121-124° C.; 1H NMR δ [(CD3)2SO]: 10.86 (s, 10.42 (s, 1H), 9.04 (s, 1H), 8.87 (s, 1H), 8.67 (s, 1 H), 8.24 (d, J=2.2 Hz, 1H), 7.89 (dd, J=8.8, 2.2 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 4.16-4.04 (m, 4H), 3.32 (d, partially obscured by water peak, 2H), 1.26 (t, J=7.0 Hz, 6H). Anal. Calcd for C19H20Cl2N5O4P.H2O: C, 45.43; H, 4.42; N, 13.94%. Found C, 45.37; H, 4.20; N, 13.81%.
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].Br[C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([Br:16])[C:9]=2[N:10]=1.[OH-].[Na+].O1CCCC1>O>[Br:16][C:11]1[C:9]2[N:10]=[C:6]([S:4][CH2:1][CH:2]=[CH2:3])[S:7][C:8]=2[CH:14]=[C:13]([CH3:15])[CH:12]=1
Reactant: Cc1cc(Br)c2nc(Br)sc2c1
Reactant: C=CCS
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCSc1nc2c(Br)cc(C)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
1.0 g of allyl mercaptan prepared above, 3.1 g of 2,4-dibromo-6-methyl-benzothiazole, 0.4 g of sodium hydroxide, 10 ml of tetrahydrofuran and 10 ml of water were mixed together and the obtained mixture was stirred for 3 hours at room temperature and then extracted with ethyl acetate. The extract was dried with anhydrous sodium sulfate and evaporated to obtain the title compound in a liquid state (Yield: 92.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[F:16][CH:17]([F:28])[O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=1>>[F:28][CH:17]([F:16])[O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[C:7]([CH3:14])[C:6]=3[CH:15]=2)=[O:26])=[N:23][CH:24]=1
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Reactant: CC1=C(CO)CCCc2ccc(N)cc21
Product: CC1=C(CO)CCCc2ccc(NC(=O)c3ccc(OC(F)F)cn3)cc21

Procedure:
In a manner similar to the procedure of step 3A, (E)-(2-amino-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methanol from preparation J was coupled with 5-(difluoromethoxy)picolinic acid from preparation K to afford the titled compound of step 46A. LCMS (M+H)+=375.27, 1H NMR (500 HMz, chloroform-d) δ 9.81 (s, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.6, 0.5 Hz, 1H), 7.68-7.64 (m, 2H), 7.55 (dd, J=8.1, 2.3 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 6.81-6.51 (m, 1H), 4.39 (s, 2H), 2.56-2.51 (m, 2H), 2.14 (s, 3H), 2.10 (quin, J=7.1 Hz, 2H), 2.00-1.96 (m, 2H), 1.89 (br. s., 1H).