Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[N:5]([CH:12]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:23]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:6][CH:7](OC)OC)[CH3:2].Cl>CC(C)=O.O>[CH2:1]([O:3][C:4]([N:5]1[CH:6]=[CH:7][C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[C:25]([O:28][CH3:29])[CH:26]=2)[CH:12]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)=[O:38])[CH3:2]
Reactant: CCOC(=O)N(CC(OC)OC)C(Cc1cccc(OC)c1)c1ccc(OC)c(OCc2ccccc2)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)N1C=Cc2cc(OC)c(OCc3ccccc3)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
[1-(3-Benzyloxy-4-methoxy-phenyl)-2-(3-methoxy-phenyl)-ethyl]-(2,2-dimethoxy-ethyl)-carbamic acid ethyl ester (3.15 g, 6.01 mmol) was dissolved in acetone (125 mL) at 0° C., and 6M aqueous hydrochloric acid (25 mL) was added dropwise. After the addition was complete, the mixture was stored at 0° C. overnight (14 hours). The mixture was warmed to room temperature and stirred×4 hours. The mixture was cooled in an ice bath and diluted with water (150 mL). The mixture was extracted with ethyl acetate (3×60 mL). The combined organic extracts were washed with water (60 mL), saturated aqueous sodium chloride solution (60 mL) and dried over anhydrous magnesium sulfate. Concentration of the solvent gave an oily solid that was crystallized from ethyl acetate/hexanes to give 7-benzyloxy-6-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (1.32 g, 2.87 mmol, 48%) as a white solid.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36]5[N:37]=[C:38]([CH3:41])[O:39][CH:40]=5)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=O)=CC=1)([O-])=O.[OH-].[Li+]>C1COCC1.C(OCC)(=O)C>[OH:10][C@@:11]([C:18]1[N:19]=[N:20][N:21]([CH2:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28]([C:36]4[N:37]=[C:38]([CH3:41])[O:39][CH:40]=4)=[CH:29][C:30]([C:34]#[N:35])=[N:31]3)=[CH:26][CH:25]=2)[CH:22]=1)([C:14]([F:16])([F:15])[F:17])[CH2:12][CH3:13]
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4coc(C)n4)cc(C#N)nc3c2)nn1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4coc(C)n4)cc(C#N)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-(1-{[2-cyano-4-(2-methyl-1,3-oxazol-4-yl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (36 mg, 0.06 mmol) in THF (1.4 mL) was added lithium hydroxide 2M (150 uL, 0.3 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with an ammonium chloride solution, brine, dried over MgSO4, filtered and concentrated to yield the title compound. The crude residue was purified by flash chromatography (10% acetone-90% dichloromethane) to give the desired product. 1H NMR (400 MHz, acetone-d6): δ 8.9 (d, 1H), 8.73 (s, 1H), 8.24 (d, 2H), 8.11 (s, 1H), 7.80 (d, 1H), 6.02 (s, 2H), 5.49 (s, 1H), 2.6 (s, 3H), 2.35 (m, 1H), 2.05 (m, 1H), 0.86 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1c[nH]c2ncc(Br)nc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-bromo-7-nitro-5H-pyrrolo[2,3-b]pyrazine (5 g, 20.57 mmol) was dissolved in DMF (100 mL) under N2. Solution was cooled in an ice bath and sodium hydride (867.1 mg, 22.63 mmol) added portionwise. After 30 minutes (effervescence completed) trityl chloride (6.022 g, 21.60 mmol) was added in one portion and the mixture allowed to warm to ambient temperature (Precipitate observed after around 15 mins). Reaction mixture was poured into water and mixture stirred for 1 hour then filtered. Solid was washed with copious water then dried in a vacuum oven over 48 hours at 80° C. Taken on to the next step as is. (9.7 g, 97.3%) 1H NMR (400.0 MHz, DMSO) δ 8.46 (s, 1H), 8.40 (s, 1H), 7.38-7.36 (m, H), 7.23-7.20 (m, 8H) and 3.32 (s, 7H) ppm
Reaction SMILES: Cl[C:2]1[C:3]([NH2:12])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[NH2:18]>CN1C(=O)CCC1>[CH3:23][O:22][C:20]1[CH:19]=[C:17]([NH:18][C:2]2[C:3]([NH2:12])=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=2)[CH:16]=[C:15]([O:14][CH3:13])[CH:21]=1
Reactant: Nc1nc2ccccc2nc1Cl
Reactant: COc1cc(N)cc(OC)c1
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2nc3ccccc3nc2N)cc(OC)c1
Temperature: 145 °C
Yield: 60 %

Procedure:
3-chloroquinoxalin-2-amine (1.8 g, 10 mmol) and 3,5-dimethoxyaniline (4.6 g, 30 mmol, commercially available from Aldrich) are taken up in NMP (4.5 ml) and heated to 145° C. in the sealed tube for 3 h under N2. When TLC confirms the total consumption of the starting material, the reaction is cooled to rt and treated with EtOAc (4 ml). The first crop of solid is filtered followed by the 2nd crop. The first is recrystallised from CHCl3: EtOAc and the 2nd crop is washed with EtOAc, to afford 1.8 g (60%) of pure title compound. LC/MS: (ES+): 297.1, (ES−): 295.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([CH2:16][C:17]#[CH:18])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28]>>[OH:28][NH:27][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:16][C:17]#[CH:18]
Reactant: NO
Reactant: C#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Product: C#CCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 25 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 m, 10 mmol), 0.065 g of the product was isolated. Yield 25%; off-white solid; mp 70° C.; MS: 375.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.19 (brs, 1H), 2.90-3.00 (m, 2H), 3.55 (d, J=13.8 Hz, 1H), 3.67 (d, J=13.8 Hz, 1H), 3.89 (s, 3H), 7.18 (d, J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 7.80-7.89 (m, 1H), 8.35-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm−1): 3168 m, 3095 s, 1670 m, 1593 s.
Reaction SMILES: ClC1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[C:47]([F:60])=[C:48]([NH:53][C:54](=[O:59])[O:55][CH2:56][CH:57]=[CH2:58])[CH:49]=[CH:50][C:51]=2[F:52])=O)[CH:40]=[CH:39][N:38]=1.[CH3:61][C:62]([CH3:67])([CH3:66])[C:63](=[S:65])[NH2:64]>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:65][C:63]([C:62]([CH3:67])([CH3:66])[CH3:61])=[N:64][C:44]=2[C:46]2[C:47]([F:60])=[C:48]([NH:53][C:54](=[O:59])[O:55][CH2:56][CH:57]=[CH2:58])[CH:49]=[CH:50][C:51]=2[F:52])[CH:40]=[CH:39][N:38]=1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1F
Reactant: CC(C)(C)C(N)=S
Agent: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: C=CCOC(=O)Nc1ccc(F)c(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Yield: 17 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4-difluorophenyl}carbamate (10 g, 27.2 mmol) NBS (5.08 g, 28.6 mmol) and 2,2-dimethylpropanethioamide (3.51 g, 29.9 mmol) the title compound of Step A was obtained (2.15 g, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (br. s., 1H), 8.67 (d, J=5.3 Hz, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.27 (t, J=8.9 Hz, 1H), 7.16 (d, J=5.3 Hz, 1H), 5.89-6.01 (m, 1H), 5.34 (d, J=17.2 Hz, 1H), 5.22 (d, J=10.4 Hz, 1H), 4.60 (d, J=5.3 Hz, 2H), 1.45 (s, 9H); MS (ESI): 464 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]=[C:4]1[C:13](=O)[C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17]C)=[O:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1.Cl.[Cl:21][C:22]1[CH:29]=[C:28]([NH:30][NH2:31])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].O1CCCC1>>[Cl:21][C:22]1[CH:29]=[C:28]([N:30]2[CH:3]([CH:2]([CH3:19])[CH3:1])[CH:4]3[CH2:5][O:6][C:7]4[CH:8]=[C:9]([C:15]([OH:17])=[O:16])[CH:10]=[CH:11][C:12]=4[C:13]3=[N:31]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC(C)C)C2=O
Reactant: N#Cc1ccc(NN)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C1C2COc3cc(C(=O)O)ccc3C2=NN1c1ccc(C#N)c(Cl)c1

Procedure:
The title compound was prepared from methyl 3-(2-methylpropylidene)-4-oxochroman-7-carboxylate; Preparation 32 (260 mg, 1.0 mmol) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride; Preparation 1 (306 mg, 1.5 mmol) according to Method B and Method C. The crude product was purified by reverse-phase HPLC (30 to 95% acetonitrile/water/0.05% trifluoroacetic acid) followed by flash chromatrography (0 to 20% methanol/ethyl acetate) to give 2-(3-chloro-4-cyanophenyl)-3-isopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid (yellow solid, 18.4 mg). The title compound was largely present as (±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-isopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1H), 7.95 (d, J=7.8 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.58 (dd, J=8.2, 1.6 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 7.42 (d, J=2.3 Hz, 1H), 7.19 (dd, J=9.0, 1.6 Hz, 1H), 4.77-4.88 (m, 2H), 4.41 (dd, J=13.3, 10.5 Hz, 1H), 4.00-4.09 (m, 1H), 2.04-2.16 (m, 1H), 0.83 (d, J=7.0 Hz, 3H), 0.82 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](O)=[CH:6][C:7](=[O:15])[NH:8]2)[CH3:2].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:5]1[C:4]2[C:9](=[CH:10][C:11]([CH2:13][CH3:14])=[N:12][C:3]=2[CH2:1][CH3:2])[NH:8][C:7](=[O:15])[CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cc2[nH]c(=O)cc(O)c2c(CC)n1
Product: CCc1cc2[nH]c(=O)cc(Cl)c2c(CC)n1

Procedure:
Compound C (17.6 g) was dissolved in phosphorus oxychloride (100 ml) and the mixture was heated at reflux for 24 hours. Unreacted phosphorus oxychloride was removed by evaporation and the residue was dissolved in concentrated hydrochloric acid (100 ml) containing water (15 ml). The mixture was heated at reflux for 4 hour. The mixture was then diluted with water (500 ml) and basified with solid potassium carbonate. The resulting precipitate was collected by filtration and washed with water. The solid was purified by flash chromatography, eluting with ethyl acetate, to give 4-chloro-5,7-diethyl-1,6-naphthyridin-2(1H)-one (D) (8.9 g); m.p. 172°-174° C.; NMR (CDCl3): 1.35(dt, 6H), 2.86(q, 2H), 3.49(q, 2H), 6.83(s, 1H), 7.0(s, 1H), 12.4(broad, 1H); mass spectrum (CI, ammonia): 237 (M+H)+ ; microanalysis, found: C, 60.3; H, 5.5; N, 11.5%; C12H13ClN2O requires: C, 60.9; H, 5.5; N, 11.8%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([CH:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Reaction time: 3 h

Procedure:
A solution of 2-(benzyloxy)biphenyl-3-carbaldehyde (14.4 g, 50 mmol) in anhydrous tetrahydrofuran (180 mL) was stirred on an ice bath under nitrogen and 1M phenylmagnesium bromide in tetrahydrofuran (60 mL, 60 mmol, 1.2 equiv.) was added over 20 min. Stirring was continued for 3 hr at room temperature. The reaction mixture was poured on saturated ammonium chloride (600 mL) and extracted with ethyl acetate (800 mL). The organic extract was washed with water (2×400 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. Crude 24 (19.2 g, 105%) was used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[OH:30]OS([O-])=O.[K+].[NH4+].[OH-]>CO.O.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12](=[O:30])[CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)OC(=O)CCN1CCSC(c2ccc(Oc3ccccc3Cl)cc2)C1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CCN1CCS(=O)C(c2ccc(Oc3ccccc3Cl)cc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-{2-[4-(2-Chloro-phenoxy)-phenyl]-thiomorpholin-4-yl}-propionic acid tert-butyl ester (0.28 g; 0.65 mmol) in MeOH (10 mL) was added, dropwise, a solution of OXONE® (0.20 g; 0.32 mmol) in water (10 mL), at 0° C. The mixture was stirred for 2 hours at 0° C., and then allowed to warm to room temperature overnight. Subsequently, water, brine, and 25% aqueous NH4OH were added and the mixture extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 98:2) to afford 3-{2-[4-(2-Chloro-phenoxy)-phenyl]-1-oxo-thiomorpholin-4-yl}-propionic acid tert-butyl ester (0.19 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)\[CH2:23][C:24]([OH:26])=O)=[CH:17][CH:16]=1.Cl.C([N:38]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)\[CH2:23][C:24]([NH2:38])=[O:26])=[CH:33][CH:34]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CC(=O)O)c2ccccc2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CC(N)=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.5 %

Procedure:
A mixture of E-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionic acid (600 mg), 1-hydroxybenzotriazole ammonia complex (260 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (328 mg) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed successively with an aqueous solution of potassium carbonate and an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from tetrahydrofuran-hexane to obtain E-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropanamide (512 mg, yield 86%) as colorless crystals. m.p. 164-165° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:23])=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][Cl:33].[OH-].[Na+]>CN(C=O)C>[Cl:33][CH2:32][CH2:31][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:23])=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(C)c2ccc(O)cc2c1=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)O)cc1-n1cc(C)c2ccc(OCCCl)cc2c1=O
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-(7-hydroxy-4-methyl-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoic acid (570 mg), potassium carbonate (2.5 g) and 1-bromo-2-chloroethane (0.9 ml) in DMF (13 ml) and heated at 50° C. for 41 hours. The reaction mixture was cooled to 40° C. and 2N NaOH solution (8 ml) was added and the reaction mixture was stirred for 1.5 hours. The reaction mixture was allowed to cool and then adjusted to pH 1 using 1N HC1, the resulting solid was collected by filtration and washed with diethyl ether to yield 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoic acid as a brown solid (426 mg); NMR Spectrum: (DMSOd6) 1.14 (s, 3H), 2.27 (s, 3H), 4.01 (t, 2H), 4.41 (m, 2H), 7.14 (s, 1H), 7.50-7.57 (m, 2H), 7.73-7.78 (m, 3H), 7.96 (d, 1H), 13.05 (br s, 1H); Mass Spectrum: M+H+ 372.
Reaction SMILES: C(O)(C)(C)C.C(N(C)[C:14](=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])C1C=CC=CC=1.C(N)CN.[Li]>C(N)CC.O>[CH:14](=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCC(=O)N(C)Cc1ccccc1
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCCN
Product: CCCCCCCCCC=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
n-Propylamine solution with t-butanol. A solution of N-benzyl-N-methyldecanoic acid amide (10 g, 0.036 mol) in n-propylamine (100 mL), ethylenediamine (13 g, 0.216 mol) and t-butanol (16 g, 0.216 mol) was cooled to -18° and lithium (1.77 g, 0.252 mol), in small pieces, was added rapidly. After 15 min, the temperature raised to 12° and then lowered. After another 45 min, the reaction turned blue and after another 30 min a yellow solution was obtained. The reaction mixture was poured over 75 g of crushed ice and water (75 mL). The mixture was extracted with ether (2×75 mL) and the combined ether extracts were washed with brine (2×50 mL). The ether was evaporated and the residue was dissolved in THF (50 mL) and 3N hydrochloric acid (15 mL). The solution was heated under reflux for 2 hr and then cooled and diluted with brine (50 mL). The mixture was extracted with ether (2×75 mL) and the combined ether extracts were washed with brine (1×50 mL) and filtered through 1PS filter paper. The ether was evaporated and the residue was distilled to give 2.0 g (36%) of n-decanal having a bp 100°-105° (15 mm).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14](F)[CH:13]=1)#[N:11].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([S:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=1)#[N:11]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: SCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C=O)c(SCCc2ccccc2)c1
Temperature: 75 °C

Procedure:
Phenylethylmercaptan (2.14 ml, 16 mmol) was added to a stirred suspension of 4-cyano-2-fluorobenzaldehyde (2.23 g, 15 mmol) and potassium carbonate (2.21 g, 16 mmol) in dimethylformamide (10 ml) at room temperature under nitrogen atmosphere. The mixture was heated to 75° C. for 1 hour, then cooled and diluted with water (15 ml). A yellow solid precipitated and was filtered, washed with water and then crystallised from cyclohexane (250 ml) to give pale needles of 4-cyano-2-(2-phenylethylthio)benzaldehyde, m.p. 89° C.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][S:11]/[C:10]/2=[N:14]\[C:15]([N:17]2[CH:21]=[CH:20][N+](C)=[CH:18]2)=[O:16])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:34]=C(CNC)[CH:36]=[CH:37][CH:38]=1>C(#N)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][S:11]/[C:10]/2=[N:14]\[C:15](=[O:16])[N:17]([CH2:21][C:20]2[CH:36]=[CH:37][CH:38]=[C:33]([F:32])[CH:34]=2)[CH3:18])=[CH:7][CH:8]=1
Reactant: C[n+]1ccn(C(=O)/N=C2\SCCN2c2ccc(Cl)cc2)c1
Reactant: CNCc1cccc(F)c1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccc(F)c1)C(=O)/N=C1\SCCN1c1ccc(Cl)cc1

Procedure:
To a solution of 1-({[(2Z)-3-(4-Chlorophenyl)-1,3-thiazolidin-2-ylidene]amino}carbonyl)-3-methyl-1H-imidazol-3-ium iodide (94 mg, 0.209 mmol, Example 25B) in dry acetonitrile (3 mL) were added diisopropylethylamine (0.040 mL, 0.230 mmol) and 1-(3-fluorophenyl)-N-methylmethanamine (0.032 mL, 0.230 mmol). The mixture was heated for 2 hours, and then cooled and concentrated under reduced pressure. The residue was purified by chromatography over silica using dichloromethane:methanol 95:5 as eluent to provide the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[CH:10][CH2:9]C1=O.[OH2:19].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[OH:7][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][CH2:9][OH:19]
Reactant: O=C1CC=Cc2ccccc2O1
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCCc1ccccc1O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 20 g of lithium aluminum hydride in 200 ml of THF at 0° C. is added dropwise 84 g of 1-benzoxepin-2-one in 200 ml of THF. After addition is complete the reaction mixture is allowed to come to room temperature and stirred 11/4 hours. The reaction mixture is then chilled to 0° C. and 20 ml water, 20 ml 15% of NaOH and 60 ml H2O are sequentially added. The mixture is then diluted with ethyl acetate, acidified and filtered through celite. The EtOAc layer is separated, dried (MgSO4) and concentrated to obtain 3-(-o-hydroxyphenyl)-1-propanol as a brown oil which is used directly in the next step.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH2:18]([O:25][CH2:26][CH:27]=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:27][CH2:26][O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][CH2:4][N:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: C[C@H]1CNCCN1C(=O)OCc1ccccc1
Reactant: O=CCOCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN(CCOCc2ccccc2)CCN1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 58 %

Procedure:
A solution of phenylmethyl (2S)-2-methyl-1-piperazinecarboxylate (commercially available) (1 g, 4.3 mmol) and benzyloxyacetaldehyde (0.9 mL, 6.4 mmol) in DCM (50 mL) was stirred for 30 minutes, and then NaBH(OAc)3 (1.36 g, 6.4 mmol) was added. The reaction was stirred overnight before being quenched with 1 M NaOH. The phases were separated and the aqueous layer was extracted with DCM. The combined organics were washed with brine, dried over sodium sulfate and concentrated to a crude residue, which was purified by silica gel chromatography (5-95% EtOAc in hexane) yielding phenylmethyl (2S)-2-methyl-4-{2-[(phenylmethyl)oxy]ethyl}-1-piperazinecarboxylate (0.93 g, 58%). LCMS: (M+H)+: 369.1