Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:47][C:48](=[CH:50][CH2:51][CH2:52]/[C:53](=[CH:55]/[CH2:56][OH:57])/[CH3:54])[CH3:49].OC/C=C(/C)\CCC=C(C)C>P.[Rh].[Rh]>[CH3:47][C:48](=[CH:50][CH2:51][CH2:52][CH:53]([CH2:55][CH2:56][OH:57])[CH3:54])[CH3:49]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: [Rh]
Agent: CC(C)=CCC/C(C)=C\CO
Agent: P
Product: CC(C)=CCCC(C)CCO
Yield: 66 %

Procedure:
A number of organic synthetic reactions using metal complexes as a catalyst have been developed from old and utilized for many purposes. In particular, many reports have been made on asymmetric catalysts that are used in asymmetric syntheses typified by asymmetric isomerization and asymmetric hydrogenation. Among them, metal complexes composed of metallic rhodium and an optically active tertiary phosphine are well known as a catalyst for asymmetric hydrogenation, and a rhodium-phosphine complex using 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter abbreviated as BINAP) as a ligand is reported in J. Am. Chem. Soc., 102, pp. 7932-7934 (1980). Further, it is reported in Inoue et al., Chemistry Letters, pp. 1007-1008 (1985) that asymmetric hydrogenation of geraniol or nerol was performed by using various rhodium-phosphine catalysts to obtain citronellol in an optical yield of 66% ee.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]([CH2:15][C:16]2[S:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[C:8](=[O:14])[N:9]=[C:10](SC)[N:11]=1)(=O)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:10]3[N:11]=[C:6]([CH2:5][OH:4])[N:7]([CH2:15][C:16]4[S:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)[C:8](=[O:14])[N:9]=3)[CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: CSc1nc(COC(C)=O)n(Cc2ccc(C(F)(F)F)s2)c(=O)n1
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc(CO)n1Cc1ccc(C(F)(F)F)s1
Yield: 15 %

Procedure:
The synthesis was performed using [4-(methylthio)-6-oxo-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,6-dihydro-1,3,5-triazin-2-yl]methyl acetate synthesized in Reference Synthesis Example 330 and 1-(4-fluorophenyl)piperazine in a similar manner to Reference Synthesis Example 348 to obtain the title compound (yield: 15%) of Synthesis Example 458a and the title compound (yield: 65%) of Synthesis Example 458b.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH2:13][CH2:14][N:15]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCC1
Reactant: c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Product: c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1

Procedure:
Title compound (E2) was prepared from 7-benzyloxy-1,2,4,5-tetrahydro-benzo[d]azepine (D2) and cyclopentanone using the method described for Example 1; MS (ES+) m/e 322 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[S:27]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
To tert-butyl 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propanoate (10 g, 35.97 mmol, 1.00 equiv) in pyridine (40 mL) was added 4-methylbenzene-1-sulfonyl chloride (6.8 g, 35.79 mmol, 1.00 equiv), in portions at 0° C. The resulting solution was stirred for 4 h at 0° C. and then concentrated under vacuum. The residue was dissolved in 30 mL of dichloromethane, washed with 3×20 mL of 3% hydrochloric acid (aq) and 20 mL of brine, and then dried over sodium sulfate. The solution was concentrated under vacuum to afford 14 g (90%) of tert-butyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[C:17]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:22]=[C:23]([NH:24][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:25]=[CH:26][CH:27]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: CC(C)(C)c1cccc(N)c1
Product: CC(C)(C)c1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3-tert-butylaniline gave N2-(3-tert-butylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 23.82 min.; purity: 100%; MS (m/e): 353 (MH+); 1H NMR (CDCl3): δ 7.96 (1H, d, J=3 Hz), 7.61 (1H, ddd, J=7.5, 2.2 and 0.9 Hz), 7.49 (1H, t, J=2.5 Hz), 7.27 (1H, m), 7.18 (1H, t, J=8.1 Hz), 7.99 (1H, m), 6.94 (1H, s), 6.91 (1H, dd, J=7.5 and 2.5 Hz), 6.80 (1H, d, J=7.5 Hz), 6.72 (2H, m), 6.58 (1H, ddd, J=7.5, 2.5 and 0.9 Hz), 6.52 (1H, ddd, J=7.5, 2.5 and 0.9 Hz), 1.28 (9H, s).
Reaction SMILES: [Br:1][C:2]1[S:19][C:5]2[NH:6][C:7](=O)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:26]([NH:29][NH2:30])(=O)[CH3:27].[OH-].[Na+]>N1C=CC=CC=1.ClCCl.O1CCCC1.O>[CH3:27][C:26]1[N:6]2[C:5]3[S:19][C:2]([Br:1])=[CH:3][C:4]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:9][CH2:8][C:7]2=[N:30][N:29]=1
Reactant: CC(=O)NN
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Br)sc2N1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(Br)cc1C(c1ccccc1Cl)=NC2
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A suspension of 50 g (0.14 mol) of (1) in 2.5 ml of pyridine and 200 ml of dichloromethane is added dropwise to a suspension of 36 g (0.183 mol) of phosphorus pentachloride in 250 ml of dichloromethane at 5-10° C. with cooling. The mixture is stirred for 1 hour at 10° C. and a solution of 17 g (0.28 mol) of acetic acid hydrazide in 170 ml of tetrahydrofuran, heated to 40-50° C., is added dropwise with cooling at 10-20° C. The mixture is then stirred for 1 hour at ambient temperature and then refluxed for 5 to 18 hours. It is then cooled to ambient temperature, 380 ml water are added with cooling and the mixture is adjusted to an alkaline pH with 45% sodium hydroxide solution. The phases are separated and the aqueous phase is extracted with 100 ml of dichloromethane. 5 g of activated charcoal are added to the combined organic phases which are then stirred for 10 minutes, filtered and evaporated to dryness in vacuo. The residue is taken up in 750 ml of boiling methylethylketone, 5 g of activated charcoal are added and the resulting mixture is refluxed for another 10 min. The suspension is filtered, then 570 ml of solvent are distilled off. The mixture is allowed to cool slowly to ambient temperature and then cooled to 5° C. and stirred for 2 hours at this temperature. The product that crystallises out is filtered off, washed with 30 ml of cold methylethylketone and 50 ml of cold ethyl acetate and dried overnight at 60° C. in vacuo. Yield: 36.6 g (66%) of brotizolam.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24]N>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:19]=1[NH:24][C:2]([CH3:15])=[C:3]2[S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Reactant: NNc1ccccc1Cl
Agent: Cl
Product: Cc1[nH]c2c(Cl)cccc2c1Sc1cccc(CC(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 2-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.3 %

Procedure:
To a solution of methyl 4-(tertiarybutyloxy carbonylaminoethyl)-phenylacetate (0.500 g, 1.71 mmol) in a mixture of tetrahydrofuran (20 ml) and water (10 ml) was added aqueous lithium hydroxide (3.8 ml of a 0.50M solution, 1.90 mmol) and the resulting mixture was stirred at room temperature for 16 h. The organic solvent was removed under vacuum and the residue was diluted with water (40 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with brine (1×30 ml), dried (MgSO4) and evaporated to give the pure title compound as colourless crystals (0.460 g), m.p. 94°-95° C. δ (360 MHz, CDCl3) 1.42 (9H, s, C(CH3)3), 2.77 (2H, br, m, ArCH2CH2NHBoc), 3.35 (2H, br, m, ArCH2CH2NHBoc), 3.61 (2H, s, ArCH2CO2H), 4.57 (1H, br, s, ArCH2CH 2 NHBoc), 7.14 (2H, d, J=7.7 Hz, ArH), 7.21 (2H, d, J=7.7 Hz, ArH); m/e (CI-) 278 (100%, m-H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]2[C:17]=1[C:16](=[O:18])[CH:15]1[CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]1)C=C.[CH2:20]1[C:29]2C(=CC=CC=2)CC[CH2:21]1>>[CH2:29]([C:6]1[C:5]([OH:4])=[C:17]2[C:9]([CH:10]3[CH:15]([C:16]2=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11]3)=[C:8]([CH3:19])[CH:7]=1)[CH:20]=[CH2:21]
Reactant: C=CCOc1ccc(C)c2c1C(=O)C1CCCCC21
Reactant: c1ccc2c(c1)CCCC2
Product: C=CCc1cc(C)c2c(c1O)C(=O)C1CCCCC21

Procedure:
A solution prepared by dissolving 16.7 g of 8-allyloxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 70 ml of tetralin was refluxed under heating for 10 hours. Tetralin was distilled off under reduced pressure and then the residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:10) to obtain 12.63 g of 7-allyl-8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CS(O[CH2:18][CH2:19][C@H:20]1[C@@H:27]2[C@@H:23]([O:24][C:25]([CH3:29])([CH3:28])[O:26]2)[O:22][C@@H:21]1[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)(=O)=O.C(OCC)(=O)C.O>CN(C)C=O>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][C@H:21]3[O:22][C@@H:23]4[O:24][C:25]([CH3:28])([CH3:29])[O:26][C@@H:27]4[C@@H:20]3[CH2:19][CH2:18][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])=[CH:37][CH:36]=2)=[CH:39][CH:40]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC1(C)O[C@H]2O[C@H](CCc3ccc(-c4ccc(Cl)cc4)cc3)[C@@H](CCOS(C)(=O)=O)[C@H]2O1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)O[C@H]2O[C@H](CCc3ccc(-c4ccc(Cl)cc4)cc3)[C@@H](CCN3C(=O)c4ccccc4C3=O)[C@H]2O1
Temperature: 50 °C

Procedure:
Potassium phthalimide (0.051 g) was added in one portion to a stirred solution of the compound obtained from step j above (0.12 g) in dimethylformamide (5 mL) at room temperature under a nitrogen atmosphere. The resulting solution was heated at 50° C. for about 14 hours and then cooled to room temperature. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous sodium sulphate. The organic phase was evaporated to dryness under reduced pressure. The residue thus obtained was purified by column chromatography using 30% ethyl acetate in hexane as eluant to furnish the title compound (0.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[CH2:12][C@:11]2([CH2:26][OH:27])[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[CH2:12][C@:11]2([CH2:26][O:27][S:36]([CH3:35])(=[O:38])=[O:37])[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)NCc2cccc(Cl)c2F)C[C@@]2(CO)C[C@@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)NCc2cccc(Cl)c2F)C[C@@]2(COS(C)(=O)=O)C[C@@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (290 mg, 0.72 mmol) and Et3N (144 μL, 1.04 mmol) in CH2Cl2 (6.5 mL) at 0° C. under nitrogen atmosphere was added methanesulfonyl chloride (81 μL, 1.04 mmol) and the mixture was stirred at RT for 1 h. Et3N (48 μL, 0.35 mmol) and methanesulfonyl chloride (27 μL, 0.35 mmol) were again added and the mixture was further stirred for 0.5 h to complete the reaction. A saturated aqueous solution of NaHCO3 was added, the layers were separated and the aqueous layer extracted with CH2Cl2 (×2), dried (Na2SO4), filtered and concentrated. The material thus obtained was used in the next step without further purification. TLC, Rf (EtOAc)=0.65; MS (UPLC/MS): 477.3/479.3 [M+H]+, 521.3/523.3 [M+HCOO]—
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:20]([CH3:21])=[C:19]([CH3:22])[S:18][C:10]=3[NH:11][C:12](=O)[C:13]([CH3:16])([CH3:15])[N:14]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:20]([CH3:21])=[C:19]([CH3:22])[S:18][C:10]=3[NH:11][C:12](=[S:32])[C:13]([CH3:16])([CH3:15])[N:14]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(C)(C)C(=O)N2
Solvent: Cc1ccccc1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(C)(C)C(=S)N2

Procedure:
A round bottomed flask was charged with 5-(4-chlorophenyl)-3,3,6,7-tetramethyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-one (324 mg, 0.973 mmol) and a stir bar. Toluene (20 mL, 0.05 M) was added, followed by Lawesson's Reagent (217 mg, 0.535 mmol, 0.55 equiv), and the solution stirred at reflux 4 h. The solution was concentrated and purified by column chromatography (eluting with hexanes/ethyl acetate) to yield 5-(4-chlorophenyl)-3,3,6,7-tetramethyl-1H-thieno[2,3-e][1,4]diazepine-2(3H)-thione as a yellow amorphous solid (m/z=349) that was used in the subsequent reaction.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([O:16]C)=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].O.[OH-].[Li+].Cl>CO.O>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]
Reactant: COC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)O)cn5)C4)c3)ncnc21
Temperature: 30 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A mixture of methyl 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]-methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylate (0.31 g, 0.57 mmol), lithium hydroxide monohydrate (0.060 g, 1.4 mmol) in methanol (6.0 mL) and water (2.5 mL) was stirred at 30° C. overnight. The mixture was adjusted to pH=4 with aqueous HCl, and concentrated under reduced pressure to remove MeOH. The resulted solid was filtered, washed with water and ether, and then dried in vacuum to afford the desired product (0.25 g, 83%). LCMS (M+H)+: m/z=532.3
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][C@@H:12]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CO[C@@H](c2ccc(F)cc2)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc([C@H]2CN(Cc3ccccc3)CCO2)cc1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
Under a nitrogen atmosphere, drop-wise add a solution of (6S)-4-benzyl-6-(4-fluorophenyl) morpholin-3-one (625 g, 2.19 mol) in THF (22 L) to lithium aluminum hydride in THF (1M in THF, 5.0 L, 5 mol) while maintaining the temperature at 20° C. Heat the mixture to 70° C. and stir for 1.5 h. Cool the mixture to 0° C. and add H2O (200 mL) to quench the reaction, followed by aqueous NaOH (4 M, 1.25 L), then add more H2O (600 mL). Stir the resulting mixture for 30 min; filter; and rinse the solid with EtOAc (10 L). Collect the filtrate and concentrate it under reduced pressure to provide the title compound (561 g, 94%). MS (m/z): 272 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:6](=[O:9])[CH2:7][Br:8])#[N:2].[BH4-].[Na+].C([BH3-])#N.[Na+].[H][H]>[Pt].[Pd].CO>[Br:8][CH2:7][CH:6]([C:5]1[CH:4]=[C:3]([CH:12]=[C:11]([F:13])[CH:10]=1)[C:1]#[N:2])[OH:9]
Reactant: [H][H]
Reactant: N#Cc1cc(F)cc(C(=O)CBr)c1
Agent: [Pd]
Agent: [Pt]
Agent: [BH3-]C#N
Solvent: CO
Product: N#Cc1cc(F)cc(C(O)CBr)c1

Procedure:
The 3-cyano-5-fluorophenacyl bromide from the above reaction is then dispersed in alcohol, preferably methanol, and reduced with sodium borohydride or sodium cyanoborohydride, or other reducing agents, such as hydrogen and a catalyst, e.g., platinum, palladium, or the like. The reaction yields 3-(2-bromo-1-hydroxyethyl)-5-fluorobenzonitrile which is readily converted to the formula I, 3-[2-(tert-butylamino)-1-hydroxyethyl]-5-fluorobenzonitrile or the 3-fluoro-5-[1-hydroxy-2-(isopropylamino)ethyl]-benzonitrile by reaction with t-butylamine or isopropylamine in the presence of ethanol.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH2:20][CH2:19][C:18]4(OCC[O:21]4)[CH2:17][CH2:16]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO>[C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2OC3(CCC4(CC3)OCCO4)c3ccccc32)cc1
Agent: Cl
Solvent: CO
Product: O=C1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
A mixture of 3.22 g of 3"-phenyldispiro[1,3-dioxolane-2,1'-cyclohexane-4',1"(3"H)-isobenzofuran], 350 ml of methanol and 10 ml of 5% hydrochloric acid is stirred at room temperature for 4 hours. The solvent is removed under reduced pressure and the residue crystallizes with 50 ml of water, suction filtered, washed with water and dried. Recrystallization from 200 ml of hexane provides 71.8% of product, mp 143°-145° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[CH:7]2.Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]([CH3:13])=[CH:7]2
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)n1c(C)cc2cc(F)ccc21
Temperature: 25 °C

Procedure:
To a stirred suspension of 322 g. (0.81 mole) of a 60% mineral oil dispersion of sodium hydride in 250 ml. of dry DMF was added dropwise a solution of 100 g. (0.67 mole) of 5-fluoro-2-methylindole in 300 ml. of dry DMF. The mixture was stirred at ambient temperature for thirty minutes and then treated dropwise with cooling with a solution of 121.5 g. (0.67 mole) of ethyl α-bromopropionate. Workup of the reaction mixture, after quenching with water and extraction of the product with ethyl acetate, afforded ethyl α-(5-fluoro-2-methyl-1-indolyl)-propionate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[F:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:35][CH:34]1O.[C:50]1(=[O:60])[NH:54][C:53](=[O:55])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12>C1(C)C=CC=CC=1>[O:55]=[C:53]1[C:52]2[C:51](=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:50](=[O:60])[N:54]1[CH:34]1[CH:33]([F:32])[CH2:38][CH2:37][N:36]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:35]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(OCc1ccccc1)N1CCC(F)C(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(F)C(N2C(=O)c3ccccc3C2=O)C1
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (3.0 equiv.) in toluene (0.25 M solution) was added DEAD (3.0 equiv.) at room temperature, which was stirred for 15 min. Then, (+/−)-benzyl 4-fluoro-3-hydroxypiperidine-1-carboxylate (1.0 equiv.) was added to the reaction mixture. After being stirred for 10 min, phthalimide (3.0 equiv.) was added and the reaction mixture was stirred for 15 h. The reaction mixture was extracted with ethyl acetate, which was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and filtered. After volatile materials were removed, (+/−)-benzyl 3-(1,3-dioxoisoindolin-2-yl)-4-fluoropiperidine-1-carboxylate was obtained by silica column chromatography (10% to 20% EtOAc in hexanes, 20%). LCMS (m/z): 383.0 (MH+), Rt=1.0 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[N+:10]([C:13]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16])([O-:12])=[O:11]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:13]=2[N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Yield: 74.1 %

Procedure:
Using the procedure described in Example 93, Part A, 4-methoxyaniline (43.76 mmol) and 2,4-dinitrobenzoyl chloride (48.14 mmol) yielded 10.29 g (74%) of the title compound.