Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]1([N:9]2[CH2:15][CH2:14][NH:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].C(N(CC)C(C)C)(C)C>CN(C)C=O>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:13]1[CH2:14][CH2:15][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][CH2:11][NH:12]1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: c1ccc(N2CCNNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1N1CCN(c2ccccc2)CCN1

Procedure:
A mixture of hexahydro-5-phenyl-1H-1,2,5-triazepine dihydrochloride (15.0 g), 1-fluoro-2-nitrobenzene (9.48 ml), N,N-diisopropylethylamine (36.5 ml) in N,N-dimethylformamide (150 ml) was magnetically stirred and heated at 75°-80° for 5 hours under nitrogen. The solution was evaporated under oil pump vacuum and the residual syrup was mixed with chloroform and dilute sodium hydroxide. The aqueous phase was extracted once more with chloroform and the combined chloroform extracts were dried (MgSO4). The solution was evaporated to a syrup which was subjected to an oil pump vacuum. This material in benzene was applied to a column (80×4.0 cm) of dry column grade neutral alumina (Woelm) prepacked in benzene. Elution was with benzene and monitoring of fractions was by t.l.c. on Alox 25 uv254 plates (Brinkmann) with benzene as developer. The fractions containing the major component were evaporated to a syrup which was crystallized from benzeneheptane; wt. 13.82 g (78%), mp=118°-120°. Recrystallization from benzeneheptane gave pure titled product, mp=119° -121°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:12].[O-]CC.[Na+]>C(O)C>[C:13]12([C:11](=[O:12])[CH:10]=[CH:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-fluorobenzaldehyde (6.01 ml, 56.10 mmol, Aldrich) and 1-adamantyl methyl ketone (10.00 g, 56.15 mmol) in absolute ethanol (100 ml) was treated with a solution of sodium ethoxide in ethanol (21% by weight solution; 2.08 ml, 5.61 mmol). A precipitate soon fell out of solution. After stirring at room temperature for 48 hours, the mixture was cooled to -10 ° C. and the precipitate was collected by filtration. The solid was washed with cold ethanol, dried in vacuo and recrystallized from hexane. The title compound was obtained as an off-white solid (9.20 g, 57.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].N1C=CC=CC=1.[C:19](Cl)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]>C1COCC1>[CH:34]1[C:35]2[CH:23]([CH2:22][O:21][C:19](=[O:20])[NH:5][C:4]3[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=3[O:2][CH3:1])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 5 h
Yield: 87.5 %

Procedure:
2-methoxy-4-nitroaniline (3 g, 17.8 mmol) was dissolved in THF (60 ml) and pyridine (1.6 ml, 19.6 mmol) was added. The reaction mixture was cooled to 0° C. and Fmoc-Cl (5.07 g, 19.6 mmol) was added in small portions. The reaction was allowed to come to ambient temperature and held for 5 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by recrystallisation from CH2Cl2 and MeOH to afford the title compound (6.08 g, 88%). Data: (m/z)=391 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:14]1[O:22][CH:15]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: c1ccc(C2CO2)cc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(CCNCC(O)c2ccccc2)cc1OC

Procedure:
A mixture of 100 g (0.55 mol) of 3,4-dimethoxyphenylethylamine and 66.2 g (0.55 mol) of styrene oxide in 200 ml of tetrahydrofuran was refluxed overnight. The solvent was removed in vacuo. About 500 ml of n-butyl chloride was added to the residue and the mixture cooled slightly. Filtration furnished N-[2-(3,4-dimethoxyphenyl)ethyl]-2-phenyl-2-hydroxyethylamine, m.p. 92°-93°.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH:60]1[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C@@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][CH:60]5[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: C=C[C@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (S)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino 1-N-methyl piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.93 (m, 2H) 1.18-1.31 (m, 2H) 1.50-1.80 (m, 6H) 1.83-2.00 (m, 4H) 2.17 (s, 3H) 2.71-2.95 (m, 2H) 3.29 (s, 3H) 3.67-3.87 (m, 3H) 3.94 (s, 3H) 4.89 (d, J=8.59 Hz, 1H) 5.30-5.47 (m, 2H) 6.01 (ddd, J=17.49, 12.69, 10.74 Hz, 1H) 7.41-7.54 (m, 2H) 7.82 (s, 1H) 8.12 (s, 2H) 8.30 (d, J=8.34 Hz, 1H) [M+H] calc'd for C29H38FN7O3, 552. found 552.
Reaction SMILES: C1(C[O:8][C:9](=[O:64])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([O:48]CC4C=CC=CC=4)[C:43]=3[O:56]CC3C=CC=CC=3)[CH:11]=2)C=CC=CC=1.[H][H].CCCCCC>[Pd].C1COCC1>[OH:56][C:43]1[C:44]([OH:48])=[CH:45][CH:46]=[CH:47][C:42]=1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=1)[C:9]([OH:64])=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(O)c2O)cc(C(=O)O)c1
Reaction time: 5 h
Yield: 87.1 %

Procedure:
A mixture of 2.0 g of 3-[[6-[2,3-bis(phenylmethoxy)phenyl]hexyl]oxy]-5-(octadecyloxy)benzoic acid phenylmethyl ester and 0.5 g of 10% palladium on carbon in 100 ml of THF was stirred in a hydrogen atmosphere until uptake ceased after 5 hours. The usual workup followed by trituration of the crude product with hexane gave 1.2 g (88% yield, mp 92°-94°) of 3-[[6-(2,3-dihydroxyphenyl) hexyl]oxy]-5-(octadecyloxy)benzoic acid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:35][CH2:36][O:37][CH2:38][CH2:39][CH3:40]>CN(C=O)C>[CH2:38]([O:37][CH2:36][CH2:35][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH2:39][CH3:40]
Reactant: CCCOCCCl
Reactant: O=C(Nc1ccc2c(c1)NCCC2)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOCCN1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-(1,2,3,4-Tetrahydroquinolin-7-yl)-1,1′-biphenyl-4-carboxamide (Example 24) (66 mg, 0.2 mmol), potassium carbonate (41 mg, 0.3 mmol), potassium iodide (100 mg, 0.6 mmol) and 2-chloroethyl-n-propyl ether (38 ul, 0.3 mmol) in DMF (1 ml) were heated at 60° C. for 17 h then 100° C. for 48 h. After cooling to ambient temperature the reaction mixture was purified on a silica SPE column. Elution with 8% EtOAc/60-80° C. petroleum ether gave the title compound as a yellow solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.93 (d, 2H), 7.72 (br, 1H), 7.70 (d, 2H), 7.63 (d, 2H), 7.48 (t, 2H), 7.40 (t, 1H), 7.03 (d, 1H), 6.92 (d, 1H), 6.74 (dd, 1H), 3.66 (t, 2H), 3.50 (t, 2H), 3.40 (m, 4H), 2.73 (t, 2H), 1.93 (qn, 2H), 1.58 (sx, 2H), 0.91 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([S:12][C:13]3[NH:14][C:15]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=4[N:17]=3)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([S:12]([C:13]3[NH:14][C:15]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[O:32])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: COc1ccc2nc(SC3CCCc4cc(C)cnc43)[nH]c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2nc(S(=O)C3CCCc4cc(C)cnc43)[nH]c2c1
Reaction time: 0.25 h

Procedure:
4.00 Grams of 3-methyl-8-(5-methoxy-2-benzimidazolyl)thio-5,6,7,8-tetrahydroquinoline was dissolved in 80 ml of dichloromethane, to this solution was added dropwise slowly at -10° C. a solution which was prepared by dissolving 2.37 g of meta-chloroperbenzoic acid (85%) in 30 ml of dichloromethane. After the dropwise solution was finished, the reaction mixture was stirred at -10° C. to -4° C. for 15 minutes. Water was added to the reaction mixture, then was made alkaline by adding sodium carbonate, then extracted with diethyl ether. The diethyl ether layer was washed with an aqueous solution saturated with sodium chloride, then was dried with anhydrous magnesium sulfate. The solvent was removed from the extract by evaporation, and was recrystallized from dichloromethane-diethyl ether to obtain 2.30 g of 3-methyl-8-(5-methoxy-2-benzimidazolyl)sulfinyl-5,6,7,8-tetrahydroquinoline in the form of white powdery crystals. Melting point: 114°-114.5° C. (decomposed).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[CH3:8][C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)([CH3:12])[CH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH3:12][C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)([CH3:8])[CH2:10][OH:11]
Reactant: BrCCCCCBr
Reactant: CC(C)(CO)Oc1ccc(-c2ccc(N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)(CO)Oc1ccc(-c2ccc(NCCCCCBr)cc2)cc1

Procedure:
23 g. of 1,5-dibromopentane, 25.7 g. of 2-methyl-2-[4-(4-aminophenyl)-phenoxy]-propanol (obtainable by reaction of 4-hydroxy-4'-nitro-diphenyl with 2-bromo-2-methylpropanol to 2-methyl-2-[4-(4-nitrophenyl)-phenoxy]-propanol and reduction), and 27 g. of potassium carbonate are refluxed in 400 ml. of n-butanol for 12 hours. 2-Methyl-2-[4-(p-5-bromopentylaminophenyl)-phenoxy]-propanol is formed as the intermediate, which is not isolated. Then, the solvent is distilled off, the residue mixed with water and extracted with ethyl acetate. After drying and evaporation, 2-methyl-2-[4-(4-piperidinophenyl)-phenoxy]-propanol is obtained, m.p. 158°-160°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: NCCCCO
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCO
Yield: 76.2 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 4-chloro-3-nitroquinoline (109.70 g, 525.87 mmol) and dichloromethane (500 mL). To the solution was added triethylamine (79.82 g, 788.81 mmol) and 4-amino-1-butanol (46.87 g, 525.87 mmol) to give a homogeneous, dark yellow solution. The reaction was judged to be complete after heating at reflux for 30 minutes. The solution was cooled and then partitioned between chloroform and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with chloroform (1×). The organic layers were combined and then concentrated under reduced pressure to afford of 4-[(3-nitroquinolin-4-yl)amino]butan-1-ol (104.67 g, 400.60 mmol) as a dark yellow solid. This material was used without further purification.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@@H:13]1[O:25][C@H:24]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]1[O:15][C:16](=[O:18])[CH3:17])(=O)C.O>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:16]([O:15][C@@H:14]1[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:24]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:25][C@H:13]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 85.2 %

Procedure:
Benzyl alcohol (0.57 mL, 5.5 mmol) was added to a solution of β-D-ribofuranose-1,2,3,5-tetraacetate (1.59 g, 5 mmol) and zinc chloride (681.4 mg, 5 mmol) in ethyl acetate (8 mL), and the mixture was stirred with heating to 60° C. for 2 hours. After cooling the mixture to ambient temperature, water (2 mL) was added to the resulting solution, for layer separation. The resulting organic layer was washed twice with aqueous 7% sodium hydrogen carbonate solution (2 mL) and subsequently concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography, to recover the desired 1-O-benzyl-β-D-ribofuranose-2,3,5-triacetate (1.56 g; yield of 85.1%) as a colorless solid. Melting point: 65° C.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[NH2:25][C@H:26]([C:28]([NH2:30])=[O:29])[CH3:27]>CN(C)C(=O)C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[N:23][C:2]([NH:25][C@@H:26]([CH3:27])[C:28]([NH2:30])=[O:29])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: C[C@H](N)C(N)=O
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N[C@@H](C)C(N)=O)cc1OCC2
Temperature: 90 °C
Yield: 7 %

Procedure:
A solution containing 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 317 (0.1 g, 0.3 mmol), prepared according to Example 377, and L-alaninamide HCl (0.15 g, 1.21 mmol) in N,N-dimethylacetamide (1 mL) was heated at 90° C. for 16 h. The crude reaction mixture was directly purified by rp-HPLC to provide 8 mg (7% yield) of 392. MS (ESI+) m/z 383.1 (M+H+), calcd. 383.2. 1H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 7.30 (s, 1H), 6.90 (s, 1H), 6.81 (d, J=7.4 Hz, 1H), 6.12 (s, 1H), 5.92 (dt, J=13.1, 6.5 Hz, 1H), 4.47 (q, J=5.8 Hz, 4H), 4.37-4.21 (m, 1H), 1.47 (dd, J=6.6 Hz, 6H), 1.25 (d, J=7.0 Hz, 3H)
Reaction SMILES: [Br:1][C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[CH:10]=O.C(O)(=O)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:10][C:3]2[CH2:4][C:5]([CH3:8])([CH3:9])[CH2:6][CH2:7][C:2]=2[Br:1])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC1(C)CCC(Br)=C(C=O)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)CCC(Br)=C(CN2CCN(C(=O)OC(C)(C)C)CC2)C1
Reaction time: 16 h
Yield: 72.8 %

Procedure:
To a solution of 2-bromo-5,5-dimethyl-cyclohex-1-ene carbaldehyde (1 g, 4.61 mmol) in dichloromethane (70 ml) at rt under nitrogen was added glacial acetic acid (0.29 ml, 5.1 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (0.94 g, 5.07 mmol). The reaction was stirred for 1 h before sodium triacetoxyborohydride (2.05 g, 9.68 mmol) was introduced. After 16 h, a solution of 5% NaOH (20 ml) was added and the mixture was extracted with dichloromethane. The organic layer was separated and washed with H2O, dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. Purification by column chromatography on silica eluting with 5% EtOAc/heptane provided 4-(2-bromo-5,5-dimethyl-cyclohex-1-enylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.3 g, 73%).-1H NMR (MeOD) δ 3.44 (4H, br t), 3.14 (2H, br s), 2.55 (2H, br m), 2.40 (4H, br t), 2.08 (2H, br s), 1.51 (2H, t), 1.48 (9H, s), 0.93 (6H, s).
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4](=[O:26])/[CH:5]=[C:6](/[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[C:10]([CH2:23][CH:24]=[CH2:25])[CH:9]=1)\[CH3:7])[CH3:2].[B]1OC2C(=CC=CC=2)[O:30]1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1COCC1>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4](=[O:26])/[CH:5]=[C:6](/[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])=[C:10]([CH2:23][CH2:24][CH2:25][OH:30])[CH:9]=1)\[CH3:7])[CH3:28]
Reactant: [B]1Oc2ccccc2O1
Reactant: C=CCc1cc(/C(C)=C/C(=O)N(CC)CC)ccc1OC(C)c1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)/C=C(\C)c1ccc(OC(C)c2ccccc2)c(CCCO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N,N-diethyl (E)-3-[3-allyl-4-(1-phenylethoxy)-phenyl]-but-2-enamide (2.61 g, 6.92 mmol) and Wilkinson's catalyst (tris(triphenylphosphine)rhodium (I) chloride, 64 mg, 0.069 mmol) in THF(40 mL) at 0° is added a 1.0 M solution of catecholborane in THF (7.62 mL, 7.62 mmol), via syringe. After stirring for 3 hours at 0°, the solution is quenched with methanol (15 mL), followed by addition of a solution 30% hydrogen peroxide (1.94 mL) in 3 M NaOH (18 mL). The solution is then warmed to room temperature over 3 hours. The solution is concentrated to 25 mL in vacuo, and the residue is taken up in H2O (100 ML) and extracted with ether (3×50 mL). The combined organic phase is washed with water (1×50 mL) and brine (1×50 mL), dried over MgSO4, and concentrated in vacuo. Chromatography (silica, 4:1 EtOAc/hexane) yields N,N-diethyl (E)-3-[3-(3-hydroxypropyl)4-(1-phenylethoxy)-phenyl]-but-2-enamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[C:12]([C:22](O)=[O:23])[CH:11]=1)#[N:2].[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][N:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[C:12]([C:22]([NH:34][C@@H:32]([C:29]2[CH:28]=[N:27][C:26]([CH3:25])=[N:31][CH:30]=2)[CH3:33])=[O:23])[CH:11]=1)#[N:2]
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)c(C#N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2′-cyano-4′-methyl-5-(thiazol-2-yloxy)biphenyl-3-carboxylic acid (30 mg, 0.089 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (30 mg, 0.22 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford a brown solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:14]2[CH2:16][CH2:15]2)(=O)=O)=CC=1.[C-:24]#[N:25].[Na+]>CS(C)=O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C@@H:13]([CH:14]2[CH2:15][CH2:16]2)[CH2:12][C:24]#[N:25])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](c2ccc(Cl)cc2)C2CC2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC[C@@H](c1ccc(Cl)cc1)C1CC1
Temperature: 90 °C
Yield: 87.3 %

Procedure:
A mixture of (2R)-2-(4-chlorophenyl)-2-cyclopropylethyl 4-methylbenzenesulfonate (11.00 g, 31.3 mmol) and NaCN (4.62 g, 94.3 mmol) in dimethyl sulfoxide (100 ml) is heated at to 90° C. for 3 hours. The dimethyl sulfoxide was removed in vacuo and the resulting mixture is partitioned between water (200 ml) and diethyl ether (200 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue chromatographed on silica gel eluting with ether:hexane (25:75) to afford the title compound as a colorless oil (5.62 g, 87%) which is characterized by 1HNMR, IR and mass spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.O1CCCC1.O.C(=O)([O-])[O-].[Na+].[Na+].[I:24]I>>[OH:10][C:8]1[C:7]([I:24])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([O:2][CH3:1])=[O:11]
Reactant: II
Reactant: COC(=O)c1cncc(O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cnc(I)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
To solution of 5-hydroxy-nicotinic acid methyl ester (2.50 g, 16.3 mmol) in tetrahydrofuran (50.0 mL, 616 mmol)/water (50.0 mL, 2780 mmol) was added sodium carbonate (5.19 g, 49.0 mmol) and iodine (10.4 g, 40.8 mmol). The reaction mixture was stirred at room temperature 4h. The aqueous layer containing product was separated and wash with hexane. The organic layer was neutralized to pH 7 with HCl, extracted EtOAc 4×. The combined organic layers was dried Na2SO4, concentrated. The crude product was purified by flash chromatography (EtOAc/DCM) (eluted at 40 EtOAc) to give methyl 5-hydroxy-6-iodonicotinate (81.2%) MS: (ESI+) 280.0