Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]([N:12]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:13](=[O:38])[CH2:14][N:15]1[C:21](=[O:22])[C:20]([CH3:26])([CH2:23][CH:24]=[O:25])[C:19](=[O:27])[N:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]1=2)([CH3:11])[CH3:10].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C1COCC1.Cl>[CH:9]([N:12]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:13](=[O:38])[CH2:14][N:15]1[C:21](=[O:22])[C:20]([CH3:26])([CH2:23][C:24]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:25])[C:19](=[O:27])[N:18]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]1=2)([CH3:11])[CH3:10]
Reactant: CC(C)N(C(=O)CN1C(=O)C(C)(CC=O)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CC(C)N(C(=O)CN1C(=O)C(C)(CC(=O)c2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.23 mL of 1.0M phenylmagnesium bromide in THF is added to a solution of 0.10 g (0.21 mmol) of N-Isopropyl-2-[3-methyl-2,4-dioxo-3-(2-oxoethyl)-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-phenyl acetamide, prepared as in Intermediate 9, in 2 mL of THF at 0° C. After stirring at room temperature for 60 min the reaction is diluted with 10 mL of 1N HCl and extracted with EtOAc (×3). The organic extract is washed with sat. NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to a colorless oil. The crude product is dissolved in 2 mL of CH2Cl2 and 0.092 g (0.42 mmol) of PCC added. After stirring at RT for 90 min, the reaction mixture is passed through a short plug of silica gel and concentrated in vacuo to a dark orange oil. Purification by silica gel flash chromatography (30% ethyl acetate/petroleum ether) gave 97 mg of the title compound as a white powder; 1H NMR (CDCl3 300 MHz) δ8.04 (d, 2H, J=7), 7.6-7.2 (m, 15H), 7.14 (t, 1H, J=7), 7.00 (d, 1H, J=7), 5.03 (m, 1H), 4.2 (m, 2H), 3.98 (dd, 1H, J=8,18), 3.61 (dd, 1H, J=5,18), 1.09 (dd, 1H, J=2,7); low resolution MS (FAB) m/e 546 (MH+).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH:8]1(C=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N1CCCCC1.Cl>N1C=CC=CC=1.O>[CH:8]1([CH:1]=[CH:2][C:3]([OH:5])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(O)CC(=O)O
Reactant: O=CC1CCCCC1
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)C=CC1CCCCC1
Temperature: 25 °C

Procedure:
A solution of malonic acid (30 g, 0.29 mol), cyclohexanecarbaldehyde (17.3 mL, 0.14 mol), and piperidine (2.9 mL, 0.029 mol) in pyridine (90 mL) was stirred at 70° C. for 18 h. The resulting mixture was cooled to room temperature and then treated with water (200 mL). The resulting solution was acidified to pH 2 with 1N HCl and extracted thrice with ethyl acetate (100 mL). The ethyl acetate extracts were pooled, washed successively with water and brine, then dried over sodium sulfate, filtered and concentrated to yield 3-cyclohexyl-acrylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13]
Reactant: COC(=O)CBr
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)N1CCCCC1
Yield: 98.7 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]piperidine (0.200 g, 0.465 mmol) was dissolved in acetone (30 ml) and after adding thereto anhydrous sodium carbonate (0.077 g, 0.558 mmol) and methyl bromoacetate (0.078 g, 0.512 mmol), the solution was refluxed under heating for 3 hours. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.230 g, 0.459 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.[CH3:20][O:21][CH:22]([O:26][CH3:27])[CH:23]([NH2:25])[CH3:24]>C(O)CCC>[CH3:20][O:21][CH:22]([O:26][CH3:27])[CH:23]([NH:25][C:10]1[CH2:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:6]2[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)[CH3:24]
Reactant: COC(OC)C(C)N
Reactant: S=C1CN=C(c2ccccn2)c2cc(Cl)ccc2N1
Solvent: CCCCO
Product: COC(OC)C(C)NC1=Nc2ccc(Cl)cc2C(c2ccccn2)=NC1

Procedure:
A solution of 7-chloro-1,3-dihydro-5-(2-pyridyl)-1,4-benzodiazepin-2-thione in butanol solution is refluxed with excess α-aminopropionaldehyde dimethyl acetal. After cooling excess butanol is removed by vacuum distillation and the residue is crystallized from ethyl acetate-hexane to give 2-[[7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]amino]propionaldehyde dimethyl acetal.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C@@H:10]([N:24]([O:36][CH3:37])[C:25](=[O:35])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=3)[CH2:9][CH2:8][C@@:7]4([OH:38])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.[CH3:39][Si](C=[N+]=[N-])(C)C.C(N(C(C)C)CC)(C)C.CO>C(#N)C>[CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C@@H:10]([N:24]([O:36][CH3:37])[C:25](=[O:35])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=3)[CH2:9][CH2:8][C@@:7]4([OH:38])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][CH3:39])[CH2:3][CH2:2]1
Reactant: CON(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccc2c3c1O[C@H]1[C@@H](N(OC)C(=O)Cc4ccc(Cl)c(Cl)c4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Reaction time: 13 h
Yield: 23.4 %

Procedure:
A mixture of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(N-methoxy-3,4-dichlorophenylacetamido)morphinan (197 mg, 0.35 mmol), trimethylsilyldiazomethane (10% solution in CH2Cl2, 0.57 g, 0.5 mmol), diisopropylethylamine (65 mg, 0.5 mmol), methanol (0.2 ml), and acetonitrile (2 ml) was stirred at room temperature for 13 h. After evaporation of the solvent, the residual oil was purified by preparative thin layer chromatography (1 mm thick plate, CH2Cl2 /MeOH: 10/1) to give 47 mg of amorphous solid. This was purified again by preparative thin layer chromatography (1 mm thick plate, CH2Cl2 /MeOH: 10/1) to give 25 mg of amorphous solid as desired product.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[NH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12]>>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12]
Reactant: O=C1CCCN1
Reactant: Brc1cccs1
Product: O=C1CCCN1c1cccs1
Yield: 95 %

Procedure:
Using general procedure C, 2-bromothiophene was coupled with 2-pyrrolidinone with the reaction time of 16 h. Chromatography gave 158 mg (95%) of the title compound as a solid. 1H NMR (CDCl3, 300 MHz): δ 6.94-6.86 (m, 2H), 6.53 (br s, 1H), 3.89 (t, 2H, J=7.2 Hz), 2.63 (t, 2H, J=8.1 Hz), 2.24 (p, 2H, J=7.5 Hz).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([OH:23])[CH:22]=2)[O:19][C:18]([CH3:25])([CH3:24])[CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:7][C:6]=1[F:28].[OH-].[K+]>CO.O1CCCC1>[F:28][C:6]1[CH:7]=[C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([OH:23])[CH:22]=2)[O:19][C:18]([CH3:25])([CH3:24])[CH2:17][C:16]3([CH3:26])[CH3:27])[CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:29])=[O:2]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)c(F)c3)cc(O)c2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 127.3 %

Procedure:
A solution of [2-fluoro-4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl]-acetic acid methyl ester (Intermediate 21, 0.037 g, 0.0493 mmol) in methanol (2 mL) and tetrahydrofuran (1 mL) was treated with a 2M solution of potassium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.024 g, 69%).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:30]=1)[C:18]1[CH:17]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([O:25][CH2:26][C:27](=[O:29])[CH3:28])=[CH:9][CH:10]=1.[CH2:31]1COCC1.C[Mg]Cl>CCOCC>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:30]=1)[C:6]1[CH:7]=[C:8]([O:25][CH2:26][C:27]([CH3:31])([OH:29])[CH3:28])[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([C:19]2[CH:24]=[N:23][CH:22]=[N:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Reactant: C1CCOC1
Agent: C[Mg]Cl
Solvent: CCOCC
Product: CC(C)(O)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Reaction time: 2 h

Procedure:
A 15-mL RBF was charged with the product from (S)-1-(2-amino-2′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)propan-2-one (104 mg, 258 μmol) in THF (2584 μl, 258 μmol). The flask was cooled in an ice-bath for 5 min, and methylmagnesium chloride, (258 μl of a 3.0 M solution in ether, 775 μmol) was added dropwise to it over 20 sec, resulting in a yellowish-white suspension. After 2 h, an additional portion of Grignard reagent (150 uL) was added and the ice-bath was removed. After 2 h, the mixture was quenched with saturated ammonium chloride solution and diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 40-g Redi-Sep column with 5% MeOH/DCM, then with 8% MeOH/DCM to afford 1-(((4S)-2-amino-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)oxy)-2-methyl-2-propanol as a white solid. MS m/z=419.2 [M+H]+. Calc'd for C23H23N4O4: 419.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH2:10][NH2:11].[CH2:20]1[C:22]2([CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]2)[CH2:21]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:18][CH3:19])[CH2:10][NH:11][CH2:28][CH:25]1[CH2:26][CH2:27][C:22]2([CH2:20][CH2:21]2)[CH2:23][CH2:24]1
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cccc1Cl
Reactant: O=CC1CCC2(CC1)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC[Si](CC)(CC)OC(CNCC1CCC2(CC1)CC2)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (248 mg, 0.774 mmol) in DCM (2581 μl) was added spiro[2.5]octane-6-carbaldehyde (107 mg, 0.774 mmol), AcOH (35.5 μl, 0.619 mmol) and NaBH(OAc)3 (246 mg, 1.161 mmol). The slurry mixture was stirred at room temperature for overnight. The mixture was quenched with 0.5 M NaOH and mixture was stirred at rt for 30 min. Evolution of gas was observed. The layers were separated. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in hexane to give 2-(2,6-dichlorophenyl)-N-(spiro[2.5]octan-6-ylmethyl)-2-((triethylsilyl)oxy)ethanamine
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.S(Cl)([Cl:26])=O>CN(C=O)C.C(Cl)Cl>[Cl:26][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2N2CCCCC2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.4 %

Procedure:
To a solution of 67.20D (0.2318 g, 0.73 mmol) in dry DMF (0.03 mL) and dry DCM (3 mL) was added thionyl chloride (0.13 mL, 1.8 mmol) at 0° C. The resulting solution was warmed to room temperature and monitored with TLC and LCMS. After 45 minutes, the reaction was diluted with DCM and then washed once with saturated aqueous sodium bicarbonate and once with brine. After drying over anhydrous magnesium sulfate, filtering, and removing the solvent under reduced pressure, the residue was purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 67.20E (86.3 mg, 35% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.16 (1H, m), 7.00 (4H, m), 6.72 (1H, dt, J=9.0, 3.5 Hz), 4.50 (2H, s), 3.71 (3H, s), 2.71 (4H, m), 1.34 (6H, m).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:22])[O:4]1.[CH3:23][C:24]([CH3:26])=O>>[CH:24]([NH:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:22])[O:4]1)([CH3:26])[CH3:23]
Reactant: CC(C)=O
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CN)O[C@H]2n1cnc2c(N)ncnc21
Product: CC(C)NC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21

Procedure:
coupling 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine with acetone in the presence of a fourth solvent, a second organic acid, and a second reducing agent to yield 9-((3aR,4R,6R,6aR)-6-((isopropylamino)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine.
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1)=C.C[N+]1([O-])[CH2:23][CH2:22][O:21]CC1.S(=O)(O)[O-:26].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[F:14][C:13]([F:16])([F:15])[C:5]1[CH:4]=[C:3]([CH:22]([OH:21])[CH2:23][OH:26])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: O=S([O-])O
Reactant: C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
Osmium tetroxide (2.5 wt % solution in 2-methyl-2-propanol, 1 mL) was added to a mixture of 1-ethenyl-3,5-bis(trifluoromethyl)benzene (1.85 g, 7.74 mmol) and N-methylmorpholine-N-oxide (1.13 g, 9.67 mmol) in tetrahydrofuran (35 mL) and water (15 mL) and the mixture was stirred at room temperature for 18 hours. Aqueous sodium bisulfite (saturated, 30 mL) was added and the tetrahydrofuran was evaporated under reduced pressure. The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (2.09 g, 98%). 1H NMR (400 MHz, CDCl3) δ 7.86 (2H, s), 7.82 (1H, s), 4.97 (1H, dd, J 8.0, 4.0 Hz), 3.87 (1H, dd, J 11.0, 4.0 Hz), and 3.66 (1H, dd, J 8.0, 11.0 Hz).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C@@H:8]2[CH2:12][C@H:11]([C:13]([O:15]CC)=[O:14])[C@H:10]([CH2:18][CH3:19])[CH2:9]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>>[CH:1]1([S:4]([NH:7][C@@H:8]2[CH2:12][C@H:11]([C:13]([OH:15])=[O:14])[C@H:10]([CH2:18][CH3:19])[CH2:9]2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)[C@H]1C[C@@H](NS(=O)(=O)C2CC2)C[C@H]1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing (1S,2R,4S)-ethyl 4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate (11.1 g, 38.4 mmol, Example #15, Step F) was added aqueous NaOH (1 N, 210 mL, 210 mmol). After stirring at ambient temperature for about 8 h, the reaction was acidified to about pH 1 using 6 N aqueous HCl and extracted with DCM (3×150 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give (1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylic acid with 25 mol % DCM as an excipient (10.7 g, 99%): LC/MS (Table 2, Method a) Rt=1.71 min; MS m/z: 260 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH2:6][NH:7][C:8]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=O)[CH3:2].P(Cl)(Cl)([Cl:34])=O>C(#N)C>[CH2:1]([O:3][C:4]([CH:5]1[C:21]2[C:26](=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)=[N:7][CH2:6]1)=[O:31])[CH3:2].[ClH:34]
Reactant: CCOC(=O)C(CNC(=O)Cc1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C1CN=C(Cc2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Product: Cl
Yield: 88.7 %

Procedure:
A mixture of 430 g (1.0 mole) of 2-(3,4-dimethoxyphenyl)-3-{{[(3,4-dimethoxyphenyl)methyl]carbonyl}amino}propanoic acid ethyl ester, 4300 ml of acetonitrile and 430 g of phosphorus oxychloride was refluxed for 1 hour and evaporated in vacuo. Crystallization of the residue from ethanol provided 399 g of the hydrochloride 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinoline carboxylic acid ethyl ester as a yellow solid, mp 213°-214° dec.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:36]=[CH:35][CH:34]=[CH:33][C:26]=2[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:36]=[CH:35][CH:34]=[CH:33][C:26]=2[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: C#CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-Amino-N-prop-2-ynyl-benzamide (4.20 g, 24.1 mmol) was dissolved in N,N-dimethylformamide (100 mL, 1.290 mol) and potassium carbonate (5.00 g, 36.2 mmol) was added. 2,4,5-Trichloro-pyrimidine (3.32 mL, 28.9 mmol) was added and the reaction was stirred for 48 hours. The reaction was concentrated under reduced pressure and the residue was taken up in DCM (300 mL) and washed with water (300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-prop-2-ynyl-benzamide as a pale yellow solid (298 mg, 4%). m.p.=188-191° C.; LCMS (m/e) 321 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.53 (s, 1H), 8.76 (d, 1H, J=8.5 Hz), 8.25 (s, 1H), 7.66-7.53 (m, 2H), 7.23-7.14 (m, 1H), 6.39 (bs, 1H), 4.34-4.25 (m, 2H), 2.34 (t, 1H, J=2.5 Hz). 1387c) 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-prop-2-ynyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a white solid (59 mg, 34%). m.p.=165-167° C.; LCMS (m/e) 505 M+H); 1H-NMR (CDCl3, 400 MHz) δ 10.91 (s, 1H), 8.69 (d, 1H, J=8.9 Hz), 8.11 (s, 1H), 7.55 (d, 1H, J=7.5 Hz), 7.50-7.43 (m, 1H), 7.35 (s, 1H), 7.28-7.22 (m, 1H), 7.16-7.08 (m, 1H), 7.04 (d, 1H, J=8.8 Hz), 6.87 (s, 1H), 6.32 (bs, 1H), 4.32-4.26 (m, 2H), 3.56 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.97-2.87 (m, 4H), 2.80-2.69 (m, 6H), 2.35-2.31 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].C(N(C(C)C)C(C)C)C.Cl.[NH2:34][C:35]([CH3:44])([CH3:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:34][C:35]([CH3:44])([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH3:43])=[O:19])=[C:5]2[OH:23]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Temperature: 80 °C
Yield: 60.8 %

Procedure:
Ethyl 6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (320 mg, 950 μmol, prepared according to Example 1 A-C) was dissolved in 1,4-dioxane (950 μL) and N-ethyl-N-isopropylpropan-2-amine (507 μL, 2851 μmol) before tert-butyl 2-amino-2-methylpropanoate hydrochloride (279 mg, 1425 μmol) was added. The resulting mixture was heated at 80° C. for 24 hours and then diluted with 150 mL of EtOAc. The resulting mixture was added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed with saturated aqueous NaHCO3 (2×75 mL), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (260 mg) after chromatography as an amorphous solid. MS (m/z)=394 (M+H-tert-butyl)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.[C:18]([O:22][C:23](=[O:39])[NH:24]/[C:25](/N1C=CC=N1)=[N:26]/[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[C:29]([O:28][C:27](=[O:33])[NH:26]/[C:25](/[NH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:10]2)=[CH:7][CH:8]=1)=[N:24]/[C:23](=[O:39])[O:22][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Reactant: CC(=O)N[C@@H]1CCN(c2ccc(N)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1CCN(c2ccc(N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)C1

Procedure:
N-[(3R)-1-(4-aminophenyl)pyrrolidin-3-yl]acetamide mono hydrochloride (Method 44, 3.31 g, 15 mmol), di-tert-butyl[(Z)-1H-pyrazol-1-ylmethylylidene]biscarbamate (5.91 g, 15 mmol) and triethylamine (4.17 ml, 30 mmol) in DCM (50 ml) were heated at 40° C. for 18 hours. After evaporation under reduced pressure, chromatography on silica gel with ethyl acetate/isohexane (50:50 to 100) gave di-tert-butyl[(E)-({4-[(3R)-3-(acetylamino)pyrrolidin-1-yl]phenyl}amino)methylylidene]biscarbamate, which was dissolved in DCM (80 ml) and treated with TFA (15 ml) at ambient temperature for 18 hours under nitrogen. After evaporation under reduced pressure, the residue was dissolved in MeOH (20 ml) and diluted with ether. The title compound was collected by filtration as an off white solid (1.79 g, 30% over two steps). NMR: 1.80 (s, 3H), 1.81-1.93 (m, 1H), 2.10-2.27 (m, 1H), 2.99-3.06 (m, 1H), 3.19-3.51 (m, 3H), 4.27-4.39 (m, 1H), 6.52 (d, 2H), 7.03 (d, 2H), 7.16 (s, 3H), 8.10 (d, 1H), 9.36 (s, 1H).