Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:11]([O:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6]1)(=O)C>Cl>[NH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:11]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6]1
Reactant: COC(=O)COc1cccc2c1CCC(NC(C)=O)C2
Agent: Cl
Product: NC1CCc2c(cccc2OCC(=O)O)C1
Temperature: 0 °C

Procedure:
20 mmol of methyl 6-acetylamino-5,6,7,8-tetrahydro-naphth-1-yl-oxyacetate are refluxed in 300 ml of 2N HCl for 24 hours. The product precipitates on cooling to 0° C.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Cl.[CH3:13][N:14]1[CH:18]=[C:17]([CH2:19][C:20]([NH2:22])=[S:21])[N:16]=[CH:15]1>>[CH3:13][N:14]1[CH:18]=[C:17]([CH2:19][C:20]2[S:21][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:22]=2)[N:16]=[CH:15]1
Reactant: O=C1c2ccccc2CC1Br
Reactant: Cn1cnc(CC(N)=S)c1
Agent: Cl
Product: Cn1cnc(Cc2nc3c(s2)Cc2ccccc2-3)c1

Procedure:
Starting compounds: 2-bromo-1-indanone, (1-methyl-4-imidazolyl)thioacetamide hydrochloride
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:42])([F:41])[CH2:33][S:34]([CH2:37][C:38](O)=[O:39])(=[O:36])=[O:35].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH:16][C:38](=[O:39])[CH2:37][S:34]([CH2:33][C:32]([F:41])([F:31])[F:42])(=[O:35])=[O:36])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCNC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(C(CCNC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Reaction time: 12 h

Procedure:
To a solution of 8.6 g. (0.019 mol.) of 7-amino-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 3.9 g. (0.019 mol.) of 2,2,2-trifluoroethylsulfonylacetic acid in tetrahydrofuran is added dropwise a solution of 3.9 g. (0.019 mol.) of dicyclohexylcarbodiimide in 100 ml. of tetrahydrofuran. The reaction mixture is stirred at 25° for 12 hours, then filtered and concentrated to about 10 ml. The residue is filtered and evaporated to dryness to give 7-(2,2,2-trifluoroethylsulfonylacetamido)-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Br:12][C:13]1[C:14]([C:21](O)=[O:22])=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=1.[BH4-].[Na+]>C1COCC1.CC#N.C(Cl)Cl>[Br:12][C:13]1[C:14]([CH2:21][OH:22])=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=1
Reactant: CSc1ncc(Br)c(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1ncc(Br)c(CO)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of DMF (1.554 mL, 20.07 mmol) and CH2Cl2 (49.9 mL) was cooled at 0° C. To this cold mixture was added oxalyl chloride (5.01 mL, 57.2 mmol). The resulting mixture was stirred cold (0° C.) for an additional 1 h. Volatiles were removed under reduced pressure to give a pale white solid, which was suspended in a mixture of THF (49.9 mL) and MeCN (49.9 mL). The resulting mixture was cooled in an ice bath. To this cold mixture was added 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (5 g, 20.07 mmol) in portions in the course of 1 h. The resulting mixture was aged at 0° C. for additional 30 min before cooling to −78° C. NaBH4 (10.04 mL, 20.07 mmol) (2M in triethylene glycol dimethyl ether) was added into this cold mixture in 40 min. The reaction mixture was stirred cold for 2 h then allowed to warm up in a MeOH/ice bath for another 1 h before quenching with HCl (1N). The reaction crude was allowed to stand overnight at ambient temp. Volatiles were removed under reduced pressure. The resulting mixture was basified by NaOH (1N, aq.). The separated aqueous layer was back extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated to afford an amber, viscous liquor. This amber gel was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted with a EtOAc/hexanes gradient mixture (0% to 20%). All related fractions were pooled and evaporated to give a white crystalline solid as the titled compound. LCMS calc.=235.94; found=236.88.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[CH3:11])([O-:3])=[O:2].C(=O)([O-])[O-].[Ca+2].Cl[C:18]([O:20][CH2:21][CH2:22][Cl:23])=[O:19].C(=O)=O>O1CCOCC1.O>[CH3:11][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][C:18](=[O:19])[O:20][CH2:21][CH2:22][Cl:23]
Reactant: O=C(Cl)OCCCl
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(NC(=O)OCCCl)cccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
91 g of 2-nitro-6-aminotoluene and 31 g of calcium carbonate are initially introduced into the reaction vessel in 750 ml of dioxane, and are heated up to 70° C. 87 g of β-chloroethyl chloroformate are added dropwise to this mixture in the course of two hours such that the reaction mixture refluxes gently, carbon dioxide being evolved. The mixture is subsequently stirred under reflux for a further two hours and then cooled to 35° C., and water and ice are added. The product which has precipitated is filtered off with suction, washed with water, and dried.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=1[O:19][CH3:20])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H][H]>CO.[Pd]>[CH3:1][CH:2]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[O:19][CH3:20])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(C)COc1cc([N+](=O)[O-])ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC(C)COc1cc(N)ccc1OC

Procedure:
At ambient temperature a rapidly stirred solution of methyl 3-methyl-4-(2-methoxy-5-nitrophenoxy)butyrate(400 mg) in methanol (20 mL) containing 10% palladium on carbon (40 mg) was exposed to an atmosphere of hydrogen. When uptake of hydrogen had ceased the solution was filtered and the filter cake washed with methanol. The combined filtrates were evaporated to dryness under reduced pressure, to give methyl 3-methyl-4-(2-methoxy-5-aminophenoxy)butyrate as an oil. (317 mg) m/Z 254(M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20]COC)=[C:6]([CH:19]=1)[C:7]([C:9]1[C:14]([O:15]COC)=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:19]=1)[C:7]([C:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8]
Reactant: COCOc1ccc(Br)cc1C(=O)c1ncccc1OCOC
Agent: Cl
Solvent: CO
Product: O=C(c1cc(Br)ccc1O)c1ncccc1O
Temperature: 25 °C
Reaction time: 70 h
Yield: 92.1 %

Procedure:
A mixture of 2-(5-bromo-2-methoxymethoxybenzoyl)-3-methoxymethoxypyridine (1.89 g), hydrochloric acid (10 ml) and methanol (80 ml) was stirred for 70 hours at room temperature. The reaction mixture was concentrated, which was partitioned with ethyl acetate-water. The organic layer was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 2-(5-bromo-2-hydroxybenzoyl)-3-hydroxypyridine (1.34 g) (Compound A-1).
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:24](=[O:28])[CH2:23][CH2:22][C:21]([CH3:30])([CH3:29])[C:20]=3[CH:19]=2)=[O:17])=[CH:11][CH:10]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>ClCCl>[C:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:24](=[O:28])[CH2:23][CH2:22][C:21]([CH3:30])([CH3:29])[C:20]=3[CH:19]=2)=[O:17])=[CH:13][CH:14]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)Cc1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)CCC(=O)c2ccc(C(=O)Oc3ccc(CC(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 29.7 %

Procedure:
A solution of 8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 4-(tert-butoxycarbonylmethyl)phenyl ester (Compound 19, 0.11 g, 0.229 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.85 mL and stirred at ambient temperature for 2.5 h. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with ethyl acetate (×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a solid which was subjected to flash column chromatography over silica gel (230-400 mesh) using ethyl acetate as the eluent to afford the title compound (0.024 g, 25%).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][C:13]1[CH2:18][CH2:17][CH2:16][C:15]([CH3:20])([CH3:19])[C:14]=1/[CH:21]=[CH:22]/[C:23](/[CH3:33])=[CH:24]/[CH:25]=[CH:26]/[C:27](/[CH3:32])=[CH:28]/[C:29]([OH:31])=O.[C:34]([O:39][C:40]1[CH:45]=[C:44]([OH:46])[CH:43]=[CH:42][C:41]=1[NH2:47])(=[O:38])[CH2:35][CH2:36][CH3:37]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:34]([O:39][C:40]1[CH:45]=[C:44]([OH:46])[CH:43]=[CH:42][C:41]=1[NH:47][C:29](=[O:31])/[CH:28]=[C:27](\[CH3:32])/[CH:26]=[CH:25]/[CH:24]=[C:23](\[CH3:33])/[CH:22]=[CH:21]/[C:14]1[C:15]([CH3:19])([CH3:20])[CH2:16][CH2:17][CH2:18][C:13]=1[CH3:12])(=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: CCCC(=O)Oc1cc(O)ccc1N
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCC(=O)Oc1cc(O)ccc1NC(=O)/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of EDCI (0.023 g, 0.12 mmol) in anhydrous DMF (5 mL) was added a solution of retinoic acid (0.031 g, 0.10 mmol) in anhydrous DMF (5 mL). The mixture was stirred at room temperature for 0.5 h. A solution of 2-amino-5-hydroxy-phenyl butanoate (KCBG05, 0.020 g, 0.12 mmol) and DMAP (cat.) in anhydrous DMF (2 mL) was added to the mixture, and again stirred for 4 h. The reaction was quenched with NH4Cl (aq.), extracted with EtOAc (2×30 mL). The extracts were washed with H2O (2×30 mL), dried over anhydrous Na2SO4, and evaporated. The residue was purified by flash column chromatography over silica gel (EtOAc:hexane=1:6) to give 2-[(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)-nona-2,4,6,8-tetraenoylamino]-5-hydroxyphenyl butanoate (KCBG10, 0.038 g, 78%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1([CH2:18][OH:19])[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.CN([CH:23]=[O:24])C>CCCCCC>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1([C:18]([O:24][CH3:23])=[O:19])[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: CN(C)C=O
Reactant: CN1CCC(CO)(c2cc(F)ccc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: COC(=O)C1(c2cc(F)ccc2F)CCN(C)CC1
Temperature: 90 °C
Yield: 92 %

Procedure:
NaH (158 mg, 6.56 mmol) was added to 4-(2,5-difluorophenyl)-4-hydroxymethyl-1-methylpiperidine (1.45 g, 6.56 mmol) in DMF (20 mL). The slurry was heated to 90° C. for 6 h. The reaction was diluted with hexane (200 mL), washed with water (200 mL), brine (50 mL), dried (MgSO4), and concentrated to yield 1.21 g (92%) of the title compound as a white crystalline solid; 1H NMR (400 MHz, CDCl3) δ 6.98 (dd, 1H), 6.54 (dt, 1H), 6.48 (dd, 1H), 4.37 (s, 2H), 2.84 (m, 2H), 2.31 (s, 3H), 1.97 (4H, pentuplet), 1.71 (m, 2H) ppm.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:13][CH2:14][CH3:15])=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C=O)C>[CH2:14]([O:13][C:4]1[C:3]([CH2:2][N:20]2[C:19](=[O:21])[C:18]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]3[C:16]2=[O:26])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:6][N:5]=1)[CH3:15]
Reactant: CCOC(=O)c1onc(OCC)c1CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)c1onc(OCC)c1CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 60 %

Procedure:
A solusion of ethyl 4-bromomethyl-3-ethoxyisoxazole-5-carboxylate (5 g, 17.9 mmol) in DMF (85 mL) was added to a suspension of potassium phthalimid (3.6 g, 19,7 mmol) in DMF (125 mL) at 90° C. The resulting mixture was stirred at 90° C. for 40 min, then cooled and concentrated in vacuo. Water (250 mL) was added and the aqueous phase was extracted with diethylether (2×200 mL). The organic extracts were dried (MgSO4) and concentrated in vacuo to give a crude product which was recrystallized (EtOH) to yield the title compound (3.70 g, 60%): mp 93-94° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16](C(OCC(Cl)(Cl)Cl)=O)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.Br.[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1C2CCC1CC(Sc1ccc(F)cc1)C2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1ccc(SC2CC3CCC(C2)N3)cc1
Temperature: 110 °C

Procedure:
A mixture of 3-(4-fluorophenylsulfanyl)-8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo-(3.2.1)-octane (the compound of Preparation 37, 10.28 g, 24.92 mmol), 48% HBr (20 mL), and acetic acid (80 mL) was heated to 110° C. for 78 h. The reaction was adjusted to pH 11 by addition of 4 N sodium hydroxide and extracted with methylene chloride. The organic phase was filtered through Diatomaceous earth, washed with brine, dried over calcium sulfate and concentrated. The residue was kugelrohr distilled (110° C. (pot temperature), 1.5 mm Hg) to give 3.30 g of 3-(4-fluorophenylsulfanyl)-8-azabicyclo-(3.2.1)-octane as a yellow oil which had NMR δ7.41 (dd, J=5.5, 9 Hz, 2 H), 7.00 (long range coupled t, J=8.5 Hz, 2 H), 4.11 (s, impurity), 3.55 (br t, J=3.5 Hz, 2 H), 3.24 (sym m, 1 H), 2.58 (br s, 2 H, exchanges with D2O, should integrate for 1 H), 1.90-1.77 (m, 4 H), 1.70-1.51 (m, 4 H). This product was suitable for use without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([OH:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24].C(OCC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([CH3:16])[O:17][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](O)Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@@H](Cc1ccc(-c2ccc(Br)cc2)cc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
(2S)-1-(4′-Bromobiphenyl-4-yl)propan-2-ol (0.23 g, 0.79 mmol) and imidazole (0.11 g, 1.6 mmol) were dissolved in N,N-dimethylformamide (5 mL), and tert-butyldimethylchlorosilane (0.24 g, 1.6 mmol) was added under a nitrogen atmosphere, followed by stirring at room temperature for 1 hour. Diethyl ether was added to the reaction solution, followed by sequential washing with water and hydrochloric acid (1 M). After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.80 (hexane/ethyl acetate=10/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.25 g, 0.62 mmol) as a white solid (yield 78%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH:33]=[CH2:34]>CN(C=O)C>[C:19]1([C:8](=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:34]=[CH:33]/[C:32]([O:36][CH2:37][CH3:38])=[O:35])=[CH:3][CH:4]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)CC(=C(c2ccccc2)c2ccc(Br)cc2)CC(C)(C)C1
Reactant: C=CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A yellow solution of 16, Et3N, ethyl acrylate and dichlorobis(triphenylphosphine) palladium(II) in DMF (25 mL, anhydrous, Aldrich) was stirred overnight under N2 at 110° C. After 16 h the reaction was allowed to cool to RT, filtered, and the filtrate diluted with ether (100 mL) and water (100 mL). The ether layer was rinsed with water (2×75 mL) and brine (1×74 mL) then dried (MgSO4) and concentrated to 5.75 g of a yellow solid. The crude product was purified first by column chromatography on 250 g silica gel with 2% EtOAc/hexanes to yield 6.22 g of an impure white solid. Crystallization from hexanes (˜100 mL) afforded 2.39 g (55%) of the title compound 17 as a crystalline white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.63 (d, J=8.0 Hz, 2H), 7.59 (d, J=16.1 Hz, 1H), 7.15-7.30 (m, 7H), 6.56 (d, J=16.1 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 1.91 (s, 2H), 1.88 (s, 2H), 1.21-1.25 (m, 5H), 0.88 (s, 6H), 0.87 (s, 6H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][CH2:19]Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][CH2:19][O:10][C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1
Reactant: CN1CCCCC1CCCl
Reactant: Oc1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCCCC1CCOc1ccc(Cl)cc1

Procedure:
200 ml of 50% aqueous sodium hydroxide solution and 1 g of triethylbenzylammonium chloride are added to a solution of 12.8 g of p-chlorophenol in 100 ml of CH2Cl2 ; 16.2 g of 1-methyl-2-(2-chloroethyl)-piperidine are added dropwise, while stirring; and the reaction mixture is stirred for a further one hour. After customary working up, 1-methyl-2-(2-p-chlorophenoxyethyl)-piperidine is obtained. Hydrochloride, m.p. 139°-140°.
Reaction SMILES: [N:1]1([C:6]2[N:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]([C:16]([OH:18])=O)[C:9]3=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>O.CN(C)C=O.O1CCCC1>[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:16]([C:10]2[C:9](=[O:19])[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:7]=3)[NH:12][CH:11]=2)=[O:18])=[CH:37][CH:36]=1
Reactant: O=C(O)c1c[nH]c2ccc(N3CCCC3)nc2c1=O
Reactant: COc1ccc(CN)cc1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2c[nH]c3ccc(N4CCCC4)nc3c2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of 6-pyrrolidino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (80 mg, 0.3 mmol) and triethylamine (0.11 mL, 0.8 mmol) in 5:1 tetrahydrofuran: N,N-dimethylformamide (6 mL) at 0° C. was added ethyl chloroformate (0.09 mL, 0.9 mmol). After stirring at 0° C. for 0.5 h, 4-methoxybenzylamine (0.1 mL, 0.8 mmol) was added. The reaction mixture was allowed to ambient temperature and stirred for 0.5 h. Water was added and the resulting precipitate collected, washed with water and ether and dried. The solid was combined with 1N NaOH (5 mL) and ethanol (2 mL) and heated at reflux for 0.25 h. The reaction mixture was cooled in in ice bath, 3N HCl was added to achieve pH 8, and the precipitate collected, rinsed with water and ether and dried to give 69 mg of N-(4-methoxybenzyl) 6-pyrrolidino-4-oxo-1,4-dihydro-1,5-naphthyri-dine-3-carboxamide; m.p. 270-272° C. Compound 8.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.[CH:25]1([CH2:28][N:29]2[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]2)[CH2:27][CH2:26]1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:34][C:32]2[CH:31]=[N:30][N:29]([CH2:28][CH:25]3[CH2:27][CH2:26]3)[CH:33]=2)=[N:3][CH:4]=1
Reactant: Nc1cnn(CC2CC2)c1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Nc4cnn(CC5CC5)c4)ncc3Cl)CC2C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 271.2 %

Procedure:
To a solution of tert-butyl 5-[(2,5-dichloropyrimidin-4-yl)amino]-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.10 g, 2.95 mmol) and 1-(cyclopropylmethyl)pyrazol-4-amine (38.5 mg, 0.28 mmol) in dioxane (10 mL) was added 2,2,2-trifluoroacetic acid (61.8 mg, 0.54 mmol). The reaction mixture was stirred at 100° C. overnight, then adjusted to pH=10 with a saturated Na2CO3 solution, and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as a pale yellow solid (0.36 g, 26%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)c1cc(F)cc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.3 %

Procedure:
To a colorless stirred solution of 3′,5′-difluoroacetophenone (50.00 g, 320.24 mmol) in methanol (320 mL), sodium borohydride (3.41 g, 86.47 mmol, 0.27 eq) was added portion wise over 20 minutes at room temperature under inert atmosphere (Ar). Then the reaction mixture was stirred for 45 min at room temperature and then quenched carefully by the addition of a saturated aqueous ammonium chloride solution (150 mL). The extraction was carried out with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give the title compound (50.29 g, 99%) as a colorless oil. The alcohol was used as such in the subsequent step.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C@@:17]3([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]3)[C:16]3[CH:15]=[C:14]([Cl:24])[N:13]=[C:12]([F:25])[C:11]=3[O:10][C:7]2=[CH:8][CH:9]=1)=[N+]=[N-].[BH4-].[Na+].O>CO>[Cl:24][C:14]1[N:13]=[C:12]([F:25])[C:11]2[O:10][C:7]3[C:6]([C@@:17]4([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]4)[C:16]=2[CH:15]=1)=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3
Reactant: [N-]=[N+]=Nc1ccc2c(c1)[C@@]1(CCOC(N)=N1)c1cc(Cl)nc(F)c1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c2cc(Cl)nc1F
Reaction time: 0.17 h
Yield: 44.4 %

Procedure:
To a solution of (S)-7-azido-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-2′-amine (0.86 g, 2.384 mmol) in MeOH (15 mL) in a water bath was added sodium borohydride (0.420 ml, 11.92 mmol) in one portion. The resulting mixture was kept in the water bath and stirred for 10 min. The reaction went to completion and was carefully quenched with water, diluted with DCM and washed with 9:1 NH4OH/sat NH4Cl (10 mL). The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-5% MeOH/DCM to afford a pale yellow solid as (S)-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.354 g, 1.058 mmol, 44.4% yield).