Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14](O)=[O:15])=[CH:13][C:9]=2[C:8]([NH:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[N:7]1)=[O:5])[CH3:2].O=S(Cl)Cl.[C:33]([NH2:42])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:35])[CH3:34].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14](=[O:15])[NH:42][C:33]([CH3:35])([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH3:34])=[CH:13][C:9]=2[C:8]([NH:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccccc2[N+](=O)[O-])c2cc(C(=O)O)sc21
Reactant: CC(C)(N)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)n1nc(NC(=O)c2ccccc2[N+](=O)[O-])c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 1.995 g (4.93 mmol) of 3-(2-Nitro-benzoylamino)-thieno[2,3-c]pyrazole-1,5-dicarboxylic acid 1-ethyl ester in toluene (35 mL) a total volume of 7.5 ml of SOCl2 was added in a step-wise manner. The suspension so obtained was heated at 80° C. for 7 hours and then evaporated to dryness. The solid was taken up with toluene and dried up twice. Next the solid was dissolved in dichloromethane (30 mL) and added drop-wise to a solution of 1.334 g (9.86 mmol) of cumylamine and DIEA (3.37 mL, 19.73 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred and allowed to reach room temperature overnight, washed with 1 N HCl, brine, water, dried up with Na2SO4 and evaporated to dryness. The crude was then purified by silica gel chromatography (flash chromatography column) eluting with dichloromethane-methanol 99:1. The titled compound was so isolated as a colourless solid (1.80 g 70%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[N+:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[C-:9].C1CCN2C(=NCCC2)CC1.CC(O)=O>O1CCOCC1>[N:3]1[CH:4]=[CH:5][N:1]2[C:2]=1[CH:6]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[CH:9]2
Reactant: O=Cc1ncc[nH]1
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2nccn2cn1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of imidazole-2-carboxaldehyde (2.3 g, 23.4 mmol) in 50 mL dioxane is added to ethyl isocyanoacetate (2.9 g, 25.8 mmol) and DBU (3.9 g, 25.8 mmol). After stirring at RT for 5 days, the reaction is neutralized with 10% AcOH. The solvent is removed in vacuo. The residue is taken up in EtOAc/H2O, the aqueous layer is extracted with CHCl3, dried (MgSO4), filtered and concentrated. The residue is purified by chromatography (Biotage 40M, eluting with 5% MeOH/EtOAc). Ethyl imidazo[1,2-c]pyrimidine-7-carboxylate is obtained (1.4 g, 32%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ9.14, 8.43, 7.88, 7.81, 4.54-4.48, 1.49-1.44.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].Br[CH:16]([C:22]1[CH:27]=[CH:26][C:25]2[O:28][CH2:29][O:30][C:24]=2[CH:23]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CCOCC>[C:6]([C:5]1[CH:10]=[CH:11][C:2]([O:1][CH:16]([C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]([CH2:12][CH2:13][CH3:14])[CH:4]=1)([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: CCCc1cc(C(=O)OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a nitrogen flushed 5 L three neck round bottom flask fitted with a mechanical stirrer, condenser, and a nitrogen inlet was charged 326 g (1.68 mol) of methyl 4-hydoxy-3-n-propylbenzoate, 507.6 g (1.73 mol) of ethyl α-bromo-3,4-methylenedioxyphenylacetate from above, 235 g (1.70 mol) of anhydrous potassium carbonate, and 1.7 L of acetone. The mixture was refluxed with vigorous stirring for 9 hr. The suspension was allowed to cool to ambient temperature and stirred overnight. The mixture diluted with 2 L of ether, cooled to 0° C. and filtered through Super-CelR. The cake washed with ether and the combined filtrate concentrated. The residue was redissolved in ether and the organic layer washed with once with 1N HCl, saturated sodium bicarbonate solution, 10% sodium bisulfite solution, brine, dried with magnesium sulfate, treated with charcoal and filtered through a plug of silica. The pale yellow solution was concentrated to 697.3 g (theoretical 678 g) of a thick yellow oil which was used without purification in the next step. NMR was consistent with the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C@@H:22]3[CH2:24][C@H:23]3[C:25](N(OC)C)=[O:26])=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1)#[N:2].C(C1C=C2C(=CC=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2[C@@H]1C[C@H]1C=O)#N>>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C@@H:22]3[CH2:24][C@H:23]3[CH:25]=[O:26])=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: CON(C)C(=O)[C@@H]1C[C@H]1c1cn(S(=O)(=O)c2ccc(C)cc2)c2cc(C#N)ccc12
Agent: Cc1ccc(S(=O)(=O)n2cc([C@@H]3C[C@H]3C=O)c3cc(C#N)ccc32)cc1
Product: Cc1ccc(S(=O)(=O)n2cc([C@@H]3C[C@H]3C=O)c3ccc(C#N)cc32)cc1
Yield: 37 %

Procedure:
Racemic [trans-2-[6-cyano-1-(p-toluenesulfonyl)indol-3-yl]-cyclopropane carboxaldehyde was prepared in a 37% yield from racemic [trans-2-[6-cyano-1-(p-toluenesulfonyl)indol-3-yl]cycloprop-1-yl]-N-methoxy-N-methyl-carboxamide in a similar manner to [trans-2-[5-cyano-1-(p-toluenesulfonyl)indol-3-yl]cyclopropane-carboxaldehyde in Example 1. 1H NMR (400 MHz, DMSO-d6) 9.11 (1H, d, J=5.5 Hz), 8.33 (1H, d, J=1.0 Hz), 7.99 (3H, m), 7.88 (1H, d, J=8.1 Hz), 7.69 (1H, dd, J=8.2, 1.4 Hz), 7.41 (2H, d, J=8.0 Hz), 2.76 (1H, m), 2.33 (3H, s), 2.14 (1H, m), 1.70 (2H, m); MS m/e 363 (M−H)−. Anal calcd. for C20H16N2O3S: C, 65.91; H, 4.42; N, 7.68. Found: C, 65.91; H, 4.45; N, 7.47.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Br[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.[H-].[Na+]>CN(C=O)C.[NH4+].[Cl-]>[N:1]1([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2nnc3ccccc32)cc1
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a solution of benzotriazole (1.14 g, 9.6 mmol) in DMF (25 mL) at 0° C. was added methyl 4-bromomethylbenzoate (2.22, 9.6 mmol) and NaH (12.25 mmol, 60% in oil). After stirring for 2 h, the mixture was diluted with aqueous NH4Cl, extracted with EtOAc. The EtOAc extract was washed H2O (3×), dried (MgSO4) and concentrated. The residue was chromatographed to give 1.32 g (51%) of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:30])=[C:16]([C@:18]2([CH3:29])[CH2:23][S:22](=[O:25])(=[O:24])[C:21]([CH3:27])([CH3:26])[C:20]([NH2:28])=[N:19]2)[CH:17]=1>>[NH2:28][C:20]1[C:21]([CH3:26])([CH3:27])[S:22](=[O:24])(=[O:25])[CH2:23][C@:18]([C:16]2[CH:17]=[C:12]([NH:11][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[CH:13]=[CH:14][C:15]=2[F:30])([CH3:29])[N:19]=1
Reactant: CC1(C)C(N)=N[C@](C)(c2cc(N)ccc2F)CS1(=O)=O
Reactant: O=C(O)c1ccc(Cl)cn1
Product: CC1(C)C(N)=N[C@](C)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)CS1(=O)=O
Yield: 97.4 %

Procedure:
Prepared from 5-chloropicolinic acid (60.8 mg, 386 μmol, Eq: 1.1) and (R)-5-(5-amino-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (105 mg, 351 μmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (150 mg, 342 μmol, 97.4% yield) as a white foam. MS (ISP): m/z=439.3 [(M+H)+] and 441.2 [(M+2+H)+].
Reaction SMILES: [C:1]([N:3]=[S:4]([C:6]1[CH:23]=[CH:22][C:9]([CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:8][CH:7]=1)[CH3:5])#[N:2].C(=O)([O-])[O-:25].[K+].[K+].ClC1C=C(C=CC=1)C(OO)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(O)C>[C:1]([N:3]=[S:4]([C:6]1[CH:23]=[CH:22][C:9]([CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:8][CH:7]=1)([CH3:5])=[O:25])#[N:2]
Reactant: CS(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CCO
Product: CS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-(4-(N-cyano-S-methylsulfinimidoyl)benzyl)isoindoline-1,3-dione (preparation 6b, 5.75 g, 17.78 mmol) and potassium carbonate (7.37 g, 53.34 mmol) in ethanol (130 mL) is cooled at 0° C. and treated with meta-chloroperoxybenzoic acid (mCPBA, 5.98 g, 26.67 mmol). The reaction mixture is warmed to room temperature and stirred overnight before more mCPBA (2.39 g, 10.66 mmol) is added and the mixture is stirred for 4 h. Saturated aqueous Na2S2O3 solution is added, and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate). Yield: 2.47 g (41% of theory); ESI mass spectrum: [M+H]+=334; r.t. HPLC: 1.02 min (V003_003).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([N:5]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1)=[O:4].[H][H]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:20])[C:3]([N:5]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1)=[O:4]
Reactant: CN(C)CCN(C(=O)N(C)C)c1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCN(C(=O)N(C)C)c1ccc(N)cn1

Procedure:
N,N-Dimethyl-N'-(2-dimethylaminoethyl)-N'-(5-nitro-2-pyridyl)urea (9.68 g., 0.034 mole) is dissolved in absolute ethanol (50 ml.) containing 10% palladium-on-carbon and is hydrogenated at an initial 42 psi of hydrogen at ambient temperature for two hours. The reaction mixture is flushed with nitrogen and then is filtered under nitrogen. The filtrate is concentrated in vacuo on a steam bath to give a nearly colorless oil (8.05 g.) which partially solidifies on standing. Crystallization from acetonitrile yields 5.19 g. of the title compound, m.p. 118°-119° C.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH:13]=1)([O-])=O>O.C(O)C>[NH2:9][C:12]1[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH:13]=1
Reactant: COc1ccc2c(=O)c([N+](=O)[O-])coc2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(=O)c(N)coc2c1
Reaction time: 0.25 h

Procedure:
Sodium dithionite (140 g, 0.804 mole) was added to a suspension of 3-nitro-7-methoxy-4H-1-benzopyran-4-one (50 g, 0.261 mole) in water (330 ml) and absolute ethanol (110 ml). The reaction mixture was stirred for 15 min., concentrated at reduced pressure and filtered. The solids were washed with water and recrystallized from ethyl acetate to give light brown crystals, 159°-162°.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=2[CH:11]=O)[CH2:3]1.[NH:20]1[C:27](=[O:28])[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22]>CO>[CH3:1][C@@H:2]1[O:7][C@@H:6]([CH3:8])[C@@H:5]2[C:26]3([CH2:11][C:10]4[C:9]([N:4]2[CH2:3]1)=[CH:16][CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[CH:13]=4)[C:24](=[O:25])[NH:23][C:21](=[O:22])[NH:20][C:27]3=[O:28]
Reactant: C[C@H]1CN(c2ccc([N+](=O)[O-])cc2C=O)C[C@H](C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CO
Product: C[C@@H]1O[C@@H](C)CN2c3ccc([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)[C@@H]12
Temperature: 60 °C

Procedure:
2-[(2S,6S)-2,6-Dimethylmorpholin-4-yl]-5-nitrobenzaldehyde (298 mg, 1.12 mmol) is combined with barbituric acid (159 mg, 1.12 mmol, Aldrich) in a vial with MeOH (2 mL). The sealed reaction is heated to 60° C. on a shaker block for 21 hours and then the solvent is evaporated. The product is purified on a Biotage Flash 40M+ using a 1:1 mixture of EtOAc and toluene as eluent Product is dried under vacuum yielding a yellow-orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91, 1.24, 2.91, 3.56, 3.63, 3.83–3.91, 3.95, 4.07, 4.14–4.24, 6.85, 7.83, 7.98, 11.59, 11.89.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[O:29][C:7]2[CH:8]=[CH:9][C:10]3[C:23](=[O:24])[C@@H:22]4[C@@H:13]([CH2:14][O:15][C:16]5[C:21]4=[CH:20][C:19]([O:25][CH3:26])=[C:18]([O:27][CH3:28])[CH:17]=5)[O:12][C:11]=3[C:6]=2[CH2:5]1)=[CH2:3].[BH4-].[Na+].O>CO>[CH3:3][C:2]([C@@H:4]1[O:29][C:7]2[CH:8]=[CH:9][C:10]([C:23]([CH:22]3[C:21]4[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([O:25][CH3:26])[CH:20]=4)[O:15][CH2:14][CH2:13]3)=[O:24])=[C:11]([OH:12])[C:6]=2[CH2:5]1)=[CH2:1]
Reactant: C=C(C)[C@H]1Cc2c(ccc3c2O[C@@H]2COc4cc(OC)c(OC)cc4[C@@H]2C3=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C(C)[C@H]1Cc2c(ccc(C(=O)C3CCOc4cc(OC)c(OC)cc43)c2O)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
12-Rotenol Synthesis: Rotenone (2 g, 5 mmol) was suspended in methanol (50 mL) and was cooled to 0° C. in an ice bath. Added solid NaBH4 (770 mg, 20 mmol) in one portion and the mixture was stirred for 1 h at 0° C. The reaction mixture was allowed to come to room temperature. Water (100 mL) was added, extracted with dichloromethane (3×50 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to obtain a fluffy solid, which was purified by flash column chromatography on silica gel using EtOAc:Hexane (1:3) to afford rotenol as colorless fluffy solid (1.98 g, 98%). m. p.: 80-82° C.; 1H NMR (CDCl3): δ 7.03 (d, 1H, J=7.96 Hz, 11-H); 6.68 (s, 1H, 1-H); 6.45 (s, 1H, 4-H), 6.44 (d, 1H, J=7.96 Hz, 10-H); 5.19 (t, 1H, J=8.89 Hz, 5′H); 5.07 (s, 1H, 7′H); 4.90 (br s, 2H, 7′-H and 12-H); 4.8-4.9 (ddd, 1H, J=5.14, 5.28, 10.68 Hz, 6a-H); 4.60 (dd, 1H, J=10.08, 10.68 Hz, 6′-Hβ); 4.22 (dd, 1H, J=5.14, 10.08 Hz, 6′-Hα); 3.84 (s, 3H, 3-OCH3); 3.83 (s, 3H, 2-OCH3); 3.37 (dd, 1H, J=4.97, 5.28 Hz, 12a-H); 3.28 (dd, 1H, J=8.89, 15.67 Hz, 4′-Hβ); 2.94 (dd, 1H, J=8.89, 15.67 Hz, 4′-Hα); 1.79 (s, 3H, 8′-CH3); 13C NMR (CDCl3): δ 188.73 (C-12); 167.14 (C-9); 157.73 (C-7a); 149.23 (C-3); 147.19 (C-4a); 143.61 (C-2); 142.83 (C-6′); 129.77 (C-11); 113.14 (C-11a); 112.80 (C-8); 112.40 (C-7′); 110.09 (C-1); 104.68 (C-10); 104.63 (C-12b); 100.70 (C-4); 87.66 (C-5′); 72.04 (C-6a); 66.10 (C-6); 56.13 (OCH3); 55.69 (OCH3); 44.41 (C-12a); 31.12 (C-4′); 17.00 (C-8′).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4](=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:19]([CH3:31])[CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]>CO>[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[C:19]([CH3:31])[CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7]
Reactant: COC(=O)C(=Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1)NC(=O)OCc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 55.9 %

Procedure:
A stream of argon was passed through a solution of N-(benzyloxycarbonyl)-4-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-dehydrophenylalanine methyl ester (8.08 mmol, 3.56 g) in methanol (25 mL) in a Parr pressure vessel overnight. Then, the catalyst, (+)-1,2-bis((2S,5S)-2,5-dimethylphospholano)benzene(cyclooctadiene)rhodium (I) trifluoromethanesulfonate [[Rh(COD)(S,S)-(me)DuPHOS]+TfO-] (˜40 mg) was added under a stream of argon in a glove box. The solution was stirred under a hydrogen pressure (60 psi) at room temperature for 22 h. The resulting solution was concentrated and the crude product was purified by silica gel chromatography using a Biotage (40m) column to obtain 2 g (55% yield) of N-(benzyloxycarbonyl)-4-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-L-phenylalanine methyl ester as an amorphous white solid. EI-HRMS m/e calcd for C24H30N2O6 (M+) 442.1627, found 442.1629.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=[C:14]2[NH:28][C:29]1[N:33]([CH:34]2[CH2:39][CH2:38][CH:37]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:36][CH2:35]2)[C:32]2[CH:48]=[CH:49][C:50]([C:52](O)=[O:53])=[CH:51][C:31]=2[N:30]=1.[I-].Cl[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][N+:58]=1C.ON1C2C=CC=CC=2N=N1.C1(N)CCCC1>C(OCC)(=O)C>[CH:59]1([NH:58][C:52]([C:50]2[CH:49]=[CH:48][C:32]3[N:33]([CH:34]4[CH2:39][CH2:38][CH:37]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:36][CH2:35]4)[C:29]([NH:28][C:14]4[C:13]5[C:17](=[CH:18][CH:19]=[C:11]([Br:10])[CH:12]=5)[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[N:15]=4)=[N:30][C:31]=3[CH:51]=2)=[O:53])[CH2:57][CH2:62][CH2:61][CH2:60]1
Reactant: C[n+]1ccccc1Cl
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2c(Nc3nn(COCC[Si](C)(C)C)c4ccc(Br)cc34)nc3cc(C(=O)O)ccc32)CC1
Agent: NC1CCCC1
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(n2c(Nc3nn(COCC[Si](C)(C)C)c4ccc(Br)cc34)nc3cc(C(=O)NC4CCCC4)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N,N-Diisopropylethylamine (19.6 uL, 0.000112 mol) was added to a solution of 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-ylamino)-1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-1H-benzo[d]imidazole-5-carboxylic acid (26.8 mg, 0.0000375 mol), 2-chloro-1-methylpyridinium iodide (19.2 mg, 0.0000750 mol) and 1-hydroxybenzotriazole (10.1 mg, 0.0000750 mol) tetrahydrofuran (0.40 mL). The mixture was stirred at room temperature for 20 minutes. Cyclopentanamine (0.000112 mol) was then added and the mixture stirred for 2 hours. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and purified by flash chromatography.
Reaction SMILES: C(=O)=O.[N:4]#[C:5]Br.[CH3:7][C:8]1[C:13]([Br:14])=[C:12]([CH3:15])[C:11]([Br:16])=[C:10]([CH3:17])[C:9]=1[OH:18].C(N(CC)CC)C.C1(O)C=CC=CC=1>C(Cl)Cl.C(O)CO>[CH3:17][C:10]1[C:11]([Br:16])=[C:12]([CH3:15])[C:13]([Br:14])=[C:8]([CH3:7])[C:9]=1[O:18][C:5]#[N:4]
Reactant: N#CBr
Reactant: Cc1c(O)c(C)c(Br)c(C)c1Br
Agent: O=C=O
Solvent: ClCCl
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Cc1c(Br)c(C)c(OC#N)c(C)c1Br
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 100.5 %

Procedure:
Twenty milliliters (ml) of methylene chloride are added to a 100 ml, 3-neck roundbottom flask fitted with a thermometer, pressure equalizing dropping funnel and nitrogen inlet. The flask is cooled in a bath of dry ice and ethylene glycol until the methylene chloride reaches a temperature of -30° C. Cyanogen bromide (4.32 grams (g), 0.0408 moles) is added to the flask. A solution of 2,4,6-trimethyl-3,5-dibromophenol (10.0 g, 0.034 mole), triethylamine (3.96 g, 0.0391 mole), and 20 ml of methylene chloride is added dropwise through the dropping funnel over a 1-hour period. The reaction temperature is maintained between -25° C. and -30° C. After about 2/3 of the phenol solution is added, a solid begins to precipitate. When the addition of the phenol solution is complete, the dropping funnel is rinsed with an additional 5 ml of methylene chloride. The reaction mixture is stirred at -30° C. for 45 minutes and then is allowed to warm to room temperature over an additional 45 minutes. 0.1N aqueous HCl is added to the reaction mixture to neutralize excess cyanogen bromide and the mixture is then stirred for 5 minutes. The neutralized mixture is transferred to a separatory funnel and the organic layer is removed. The organic layer is washed with water and is dried over magnesium sulfate. The solvent is removed from the treated organic layer in vacuo to give 10.9 g of a white solid (100 percent crude yield). This material is heated to 75° C. under vacuum to remove volatiles. The material is then bulb to bulb distilled at 150° C. and 0.1 millimeters (mm) mercury to give a white solid (7.46 g, 69 percent yield) with a melting point between 126.5° and 127.5° C.
Reaction SMILES: [AlH](CC(C)C)CC(C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH2:24][CH2:23][NH:22][C:21](=O)[C@H:20]([CH3:26])[C:16]=3[NH:17][C:18]=2[CH:19]=1>C(Cl)Cl.C1COCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH2:24][CH2:23][NH:22][CH2:21][C@@H:20]([CH3:26])[C:16]=3[NH:17][C:18]=2[CH:19]=1
Reactant: C[C@H]1C(=O)NCCc2c1[nH]c1cc(F)ccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1CNCCc2c1[nH]c1cc(F)ccc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To an oven-dried flask containing dry THF (10 mL) under argon at −78° C. was added a 1 M solution of (iBu)2AlH in CH2Cl2 (16.3 mL). This mixture was stirred at −78° C. for 5 min. To this was (R)-8-fluoro-5-methyl-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one (0.236 g, 1.02 mmol) in dry THF (16 mL). The reaction mixture was stirred at rt for 72 h, cooled to 0° C., then quenched by the addition of MeOH (4.5 mL). The mixture was partitioned between CH2Cl2 and 1 M aq NaO2CCH(OH)CH(OH)CO2K. The CH2Cl2 extracts were washed with brine, and dried, filtered and concentrated to give an oil. The oil was purified by silica chromatography to give the amine. To a solution of this amine (0.105 g, 0.48 mmol) in dry MeOH (4 mL) was added fumaric acid (0.028 g, 0.24 mmol) in MeOH (2.2 mL). The mixture was stirred overnight, concentrated, and the residue was dissolved in hot MeOH from which crystalline product was recovered: mp 256-258° C.; MS (ESI+) m/z 219.1; 1H NMR (CD3SOCD3, 300 MHz) δ 10.83 (1H), 9.3-8.5 (2H), 7.35 (1H), 7.01 (1H), 6.78 (1H), 6.43 (1H), 3.22-2.70 (8H), 1.30 (3H); Anal. C 64.94, H 6.27, N 10.07.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH:14]=[N:13][NH:12][C:10]3=2)[N:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>CN(C)C=O>[Cl:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH:14]=[N:13][NH:12][C:10]3=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2ccc3cn[nH]c3c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ccnc2ccc3cn[nH]c3c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
A mixture of 9-hydroxy-1H-pyrazolo[3,4-f]quinoline (2.97 g, 16.0 mmol) and phosphorus oxychloride (24.58 g, 160 mmol) at 0° C. was treated with dimethylformamide (DMF) (15.4 ml) dropwise. After addition was complete, the viscous reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was then poured onto ice and the resulting dark brown solution was treated with decolorizing carbon and filtered, and the brown filtrate neutralized with 10M NaOH. The light brown solid which resulted was collected by filtration and air dried giving 9-chloro-1H-pyrazolo[3,4-f]quinoline (1.73 g, 53%).