Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19]Cl)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: COc1c(Cl)cnc2[nH]c(-c3ccc(OCCCl)cc3)nc12
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Cl)cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc12
Temperature: 100 °C
Yield: 7.1 %

Procedure:
6-Chloro-2-[4-(2-chloroethoxy)phenyl]-7-methoxy-3H-imidazo[4,5-b]pyridine (0.27 g, 0.8 mmol), morpholine (0.22 ml, 2.52 mmol) and Hünig's base (1.42 ml, 8.15 mmol) were dissolved in NMP (20 ml) and the mixture was heated at 100° C. for 9 h. The NMP was partly removed by evaporation, after which water was added. The precipitated crude material was purified by column chromatography (dichloromethane/methanol 95:5), giving the title product (0.022 g, 7%).
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1>>[CH3:26][C:24]1[N:25]=[C:21]([NH:20][C:4]([C:6]2[C:11]([NH:12][C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])[S:22][CH:23]=1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cnn(C)c1
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cnn(C)c2)n1

Procedure:
The title compound, was prepared in accordance with the general method of Example 78, step 2 from 6-Methyl-3-(1-methyl-1H-pyrazol-4-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-Amino-4-methylthiazole to yield the final compound as a yellow solid, MS (ISP): m/e=329.3 (M+H+).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CC(C)([O-])C.[K+].F[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1.O>CS(C)=O>[NH2:4][CH2:3][CH2:1][O:2][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:16][CH:17]=1
Reactant: NCCO
Reactant: O=C1CCC(c2ccc(F)cc2)=NN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NCCOc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 65 °C
Yield: 34.4 %

Procedure:
In a flame-dried, round-bottomed flask, ethanolamine (1.7 ml, 28.1 mmol) was dissolved in dimethylsulfoxide (9.5 ml), and potassium tert-butoxide (95%, 3.3 g, 28.1 mmol) was added to the solution. This mixture was stirred at about 65° C. for about ten minutes, and then 6-(4-fluorophenyl)-4,5-dihydro-2H-pyridazine-3-one (3.6 g, 18.7 mmol) was added. This dark-colored solution was heated to about 80° C. for about twelve hours, and was then cooled to room temperature. Water was added, and the resulting tan solid was removed by filtration. This crude solid was then purified by column chromatography (silica gel; 5% methanol/dichloromethane to 15% methanol/dichloromethane) to afford the product as a white solid (1.5 g, 34% yield). LRMS ([M+H]+)=234.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]2[N+:15]([O-])=O)=[CH:5][C:4]=1[O:18][CH3:19].COC1C=CC([C@@H]2CC=CC[C@H]2[N+]([O-])=O)=CC=1OC.[OH-].[K+].S(=O)(=O)(O)O>C(O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:18][CH3:19]
Reactant: COc1ccc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])cc1OC
Agent: COc1ccc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])cc1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Specific rotation: [ α ] D 20 = - 58.5 ° ⁢   ⁢ C ⁢   ⁢ ( c = 1 , ethanol ) . C1. (+/−)-cis-1,2-Dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene 10.0 g of (+/−)-trans-1,2-dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene and 20.0 g of potassium hydroxide are dissolved in 150 ml of ethanol and 35 ml of dimethylformamide. A solution of 17.5 ml of conc. sulfuric acid in 60 ml of ethanol is then added dropwise such that the internal temperature does not exceed 4° C. After stirring for 1 h, the mixture is added to 1 l of ice water, the precipitate is filtered off with suction, washed with water and dried, and the crude product is recrystallized from ethanol. 8.6 g of the title compound of m. p. 82.5-84° C. are obtained. C2. (+/−)-cis-1,2-Dimethoxy-4-(2-nitrocyclohexyl)benzene
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:23](=[O:36])[NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=3)[CH:14]=2)[CH:9]=[CH:8][N:7]=1)=O)C.[BH4-].[Na+]>C(O)(C)(C)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:23]([C:19]2[C:20]3[C:15](=[CH:14][C:13]([O:12][C:10]4[CH:9]=[CH:8][N:7]=[C:6]([CH2:4][OH:3])[N:11]=4)=[CH:22][CH:21]=3)[CH:16]=[CH:17][CH:18]=2)=[O:36])=[CH:26][C:27]=1[C:32]([F:34])([F:33])[F:35]
Reactant: CCOC(=O)c1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cccc2cc(Oc3ccnc(CO)n3)ccc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 523 mg (1.048 mMol) 4-[5-(4-fluoro-3-trifluoromethyl-phenylcarbamoyl)-naphthalen-2-yloxy]-pyrimidine-2-carboxylic acid ethyl ester in 13.8 ml tert-butanol, 119 mg (3.14 mMol) NaBH4 are added. This mixture is stirred for 2 h at 70° C. and then concentrated in vacuo. The residue is diluted with water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with brine, dried (Na2SO4) and concentrated. Chromatography [Combi Flash; CH2Cl2/(CH2Cl2/tertBuOH 1:1) 99:1→83:17] and trituration from DIPE gives the title compound: Anal. (+0.3H2O+0.4 DIPE): C, H, N, F; MS: [M+1]+=458; TLC (CH2Cl2/acetone 9:1): Rf=0.44.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:18]=[S:19]1(=[O:36])[CH2:24][CH2:23][N:22]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[C:21]2=[N:20]1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:35][C:32]2[CH:31]=[CH:30][C:29]([C:28]3[C:21]4=[N:20][S:19](=[O:36])(=[O:18])[CH2:24][CH2:23][N:22]4[CH:25]=[CH:26][CH:27]=3)=[CH:34][CH:33]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A mixture of 4-(tert-butyldimethylsilyloxy)phenylboronic acid (6.11 g), 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (2.23 g), triethylamine (5.61 mL), diacetoxycopper (2.93 g), and 4A MS (2.0 g) in DMF (80 mL) was stirred at room temperature overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (1.82 g) as a white solid.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH2:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl.O>CS(C)=O>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[CH2:7]
Reactant: C=C(c1ccccc1O)n1ccnc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=C(c1ccccc1OCc1ccc(Cl)cc1Cl)n1ccnc1
Yield: 93.9 %

Procedure:
To a solution of 500 g (2.69 mol) of 2-[1-(1H-imidazol-1-yl)vinyl]phenol 4 in 3 L of DMSO was added 210 g (3.22 mol) of potassium hydroxide (pellet) with stirring and the mixture was stirred at room temperature for 1 hour. The solution was cooled to 12°-18° C. and there was dropwise added a solution of 577 g (2.95 mol) of 2,4-dichlorobenzyl chloride 9 in 100 ml of DMSO in 1 hour. The mixture was allowed to stand at the same temperature with stirring for 2 hours. To the reaction mixture was dropwise added 4.5 L of water with ice-cooling in 45 minutes. The resulting mixture was stirred for 1 hour, and the precipitating crystals were collected by filtration, washed with water (0.75 L×4) and then with n-hexane (0.7 L×3), and dried in air to give 872 g (yield: 94.1%) of the titled compound 10, m.p., 90.5°-93° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13](=O)[CH3:14])[CH2:8][CH2:7][CH2:6]2.[CH2:16]([NH2:18])[CH3:17].Cl.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH:13]([NH:18][CH2:16][CH3:17])[CH3:14])[CH2:8][CH2:7][CH2:6]2
Reactant: CCN
Reactant: COc1ccc2c(c1)CCCC2C(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNC(C)C1CCCc2cc(OC)ccc21

Procedure:
The product of Example 93 (2 g) was dissolved in anhydrous MeOH (20 ml) and EtNH2 (3 ml) and the pH adjusted to ca. 8 with methanolic HCl. Sodium cyanoborohydride (500 mg) was added and an additional 2 ml methanolic HCl dropwise. The reaction was stirred under N2 for 48h then 6 N HCl added to pH<2. The methanol was removed under vacuum and the aqueous layer extracted with CH2Cl2 (2×100 ml). The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated giving 0.18 g of an oil. The neutral CH2Cl2 extract was dried (MgSO4), filtered and evaporated then partitioned between 2 N HCl and a mixture of ether/hexane. The organic layer was separated and discarded. The acidic layer was basified and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and evaporated giving an additional 1.12 g of product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([F:12])[CH:3]=1.B>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: B
Solvent: C1CCOC1
Product: OCCc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
4-Bromo-2-fluoro-phenyl-acetic acid (36 g, 154 mmol) (40.6 g, 174 mmol) was dissolved in THF (100 mL), and cooled to 0° C. in an ice-bath. Borane (1 M in THF, 200 mL, 1.2 eq) was then added dropwise. During the addition, the temperature rose slowly to 27° C. After complete addition the ice-bath was removed and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was added carefully to saturated aqueous K2CO3 (300 mL), and the obtained suspension was diluted with H2O (500 mL). The THF layer was separated and concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (2×100 mL). The residue from the concentrated THF layer was dissolved into the combined organic layers, which was washed with brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure, yielding crude material (35.6 g) as a yellow oil, which solidified to a white solid upon standing. The crude material was purified by column chromatography (SiO2; 1750 mL, 0-5% MeOH in CH2Cl2), yielding the title compound as a white solid (31.5 g, 144 mmol, 82%). 1H-NMR (CDCl3, 300 MHz): 1.50 (s, 1H); 2.95 (t, 2H); 3.92 (t, 2H); 7.18 (t, 1H); 7.28 (m, 1H)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:28]3[CH:24]([CH2:25][N:26]([C:11](=[O:13])[CH2:10][C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3c[nH]c4ccccc34)CC12
Reaction time: 1 h
Yield: 44.7 %

Procedure:
N,N'-Carbonyldiimidazole (4.05 g) is added to a solution of 2-(3-indolyl)acetic acid (4.37 g) in dry dichloromethane (100 cc), cooled to +5° C. The mixture is stirred for 1 hour at +5° C. and (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone (7.3 g) is then added. The reaction mixture is stirred at 20° C. for 20 hours, then washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 7 cm, height 40 cm), eluting with a mixture of ethyl acetate and cyclohexane (70/30 by volume) and collecting 100 cc fractions. Fractions 6 to 11 are concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from acetonitrile (50 cc). The crystals obtained are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-(3-indolyl)acetyl]-4-perhydroisoindolone (5 g) melting at 250° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Cl:9]N1C(=O)CCC1=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:9])=[C:4]([CH3:8])[N:3]=1
Reactant: Cc1cccc(N)n1
Reactant: O=C1CCC(=O)N1Cl
Product: Cc1nc(N)ccc1Cl

Procedure:
In the manner described above in Example BBM-001-065, 2-amino-6-picoline, Acros Organics (1.08 g, 0.01 mol) is treated with N-chlorosuccinimide to give 2-amino-5-chloro-6-methylpyridine as a light-yellow solid (MP 73-74° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O.[H][H]>C(OCC)(=O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(O)c(N)c1
Yield: 106 %

Procedure:
A mixture of 10.4 grams (0.05 mole) of ethyl 3-nitro-4-hydroxybenzoate, 0.3 gram of platinum oxide (catalyst) in 200 mL of ethyl acetate was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 9.6 grams of ethyl 3-amino-4-hydroxybenzoate as a solid. The NMR spectrum was consistent with the proposed structure. This 3-amino derivative, 9.0 grams (0.05 mole), was dissolved in 150 mL of ethanol and 9.7 grams (0.06 mole) of triethyl orthopropionate was added. The reaction mixture was heated at reflux for three hours, then cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:4 ethyl acetate: heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of ethyl (2-ethylbenzoxazol-5-yl)carboxylate, mp 35-37° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].C(O)(=O)C.O>C1C=CC=CC=1.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[C:14]([C:15]([CH3:17])=[O:16])[C:13]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CC(C)=O
Reactant: COc1ccc(C=O)cc1OC
Solvent: O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccc(OC)c(OC)c1)C(C)=O
Reaction time: 120 h
Yield: 51.8 %

Procedure:
To a solution of 54.8 g (0.33 mol) 3,4-dimethoxybenzaldehyde and 34.8 mg (0.3 mol) methyl acetoacetate in 20 ml benzene, were added dropwise 1.02 g (12 mmol) piperidine and 3.66 g (61 mmol) acetic acid in that order, and water was removed from the mixture by heating in a Dean-Stark apparatus until water was no longer distilled off. The solvents were distilled off from the reaction mixture, and the oil thus left was allowed to stand for five days. The crystals which separated out were collected by filtration, giving 41.1 g (52%) of methyl 2-(3,4-dimethoxy-benzylidene)acetoacetate as yellow crystals. M.P.: 93°-95° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5]([C:8]#[N:9])([CH3:7])[CH3:6])C.[H][H]>[Ni].CO>[CH3:1][O:3][C:4](=[O:10])[C:5]([CH3:7])([CH3:6])[CH2:8][NH2:9]
Reactant: CCOC(=O)C(C)(C)C#N
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COC(=O)C(C)(C)CN
Yield: 94.7 %

Procedure:
A mixture of 10 g of Raney-nickel 2800 was transferred to a 500 mL hydrogenation vessel and washed three times with 40 mL of methanol. Then, 180 mL of methanol and 25.0 g (0.177 mole) of 2-cyano-2-methylpropanoic acid ethyl ester was added and the mixture agitated on a Paar hydrogenator under a 50 psi atmosphere of hydrogen for 24 hours. The mixture was filtered through Celite, washing the filter pad with methanol, and then concentrated under reduced pressure to give 21.98 g of 3-amino-2,2-dimethyl-propanoic acid methyl ester, which was used without further purification.
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[O:14][C:13]([CH3:21])([CH3:20])[CH2:12][C:11]2=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[O:14][C:13]([CH3:21])([CH3:20])[CH:12]=[C:11]2[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Mg]Cl
Reactant: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: COc1cc2c(cc1Br)C(C(C)(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure C, tert-butylmagnesium chloride (1.0 M in THF, 45.5 mL, 45.5 mmol) was added to a solution of 6-bromo-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 4, 2.6 g, 9.1 mmol) in THF. The crude alcohol was treated with p-toluenesulfonic acid to afford the title compound as a colorless oil.
Reaction SMILES: [C:1]1([C@@H:7]([OH:11])[CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.BrC1C=CC(S([Cl:29])(=O)=O)=CC=1>C(OC)(C)(C)C.O1CCCC1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:29][CH2:9][CH2:8][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:11]
Reactant: OCC[C@H](O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: O[C@@H](CCCl)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 114.1 %

Procedure:
To a solution of (S)-1-phenyl-1,3-propanediol (125 g, 0.822 mole) in methyl tert-butyl ether (500 mL) was added triethylamine (135 mL). The reaction mixture was cooled to 0° C. and a solution of 4-bromobenzenesulfonyl chloride (230 g, 0.92 mole) in methyl tert-butyl ether (300 mL) and tetrahydrofuran (300 mL) was added dropwise over 3 hour. After the addition, the reaction mixture was stirred at 0° C. for three hours and was then warmed to ambient temperature. After stirring at ambient temperature for 18 hours, benzyltriethylammonium chloride (210 g, 0.92 mole) was added and the resulting mixture was heated at 55° C. for three hours. The reaction mixture was cooled to ambient temperature and then diluted with water. After separation of the organic phase, the aqueous phase was extracted two times with diethyl ether. The combined organic extracts were washed with 1.0 N hydrochloric acid, saturated aqueous sodium bicarbonate, water, saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure to provide an off-white solid (160 g). This solid was subjected to silica gel chromatography, eluting with ethyl acetate/hexane (1:9) to provide 110 grams (80%) of the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH3:16][N:17]1[C:21]2[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=2[C:19]([C:28]([O:30]CC)=O)=[N:18]1>C1COCC1>[CH3:5][O:4][N:3]([CH3:2])[C:28]([C:19]1[C:20]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22](=[O:27])[C:21]=2[N:17]([CH3:16])[N:18]=1)=[O:30]
Reactant: CNOC
Reactant: CCOC(=O)c1nn(C)c2c1CCCCC2=O
Agent: Cl
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)c1nn(C)c2c1CCCCC2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (650 mg, 0.67 mmol) in 2 mL of anhydrous THF under argon, 1M solution of LiN(TMS)2 in THF (1.32 mL, 1.32 mmol) at 0° C. were added dropwise. The mixture was stirred at 0° C. for 0.5 h then ethyl 1-methyl-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxylate (50 mg, 0.22 mmol) in 5 mL of anhydrous THF at 0° C. were added dropwise. Ice bath was removed and the mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture was extracted with AcOEt (2×30 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent evaporated to dryness. The crude solid was used without further purification. 52 mg (quantitative yield).
Reaction SMILES: S(=O)(=O)(O)O.S(O)([O:9][C:10]1[C:11]([NH2:17])=[N:12][C:13]([NH2:16])=[N:14][CH:15]=1)(=O)=O>O>[NH2:16][C:13]1[N:12]=[C:11]([NH2:17])[C:10]([OH:9])=[CH:15][N:14]=1
Reactant: Nc1ncc(OS(=O)(=O)O)c(N)n1
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1ncc(O)c(N)n1
Yield: 114.7 %

Procedure:
A stirred solution of 23.0 grams (0.235 mole) of concentrated sulfuric acid and about 18 mL of water was heated to reflux, and 48.5 grams (0.235 mole) of 2,4-diamino-5-pyrimidinyl hydrogen sulfate was added in one portion. Upon completion of addition, the reaction mixture was heated at reflux for ten minutes and then was immediately cooled in an ice-water bath. The resultant solid was collected by filtration, and the filter cake was washed with 100 mL of cold water. The solid was dried, yielding 34.0 grams of 2,4-diamino-5-hydroxypyrimidine hydrosulfate salt, mp 290° C., dec. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:33]=[CH:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:30]=2)O1>>[C:37]([O:36][C:34]([N:31]1[CH:32]=[CH:33][C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:30]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)n1ccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccn(C(=O)OC(C)(C)C)c3)ccn2c1=O
Yield: 62 %

Procedure:
Methyl 8-(1-(tert-butoxycarbonyl)-1H-pyrrol-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (151.0 mg, 0.51 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (89 mg, 61%). ESI-MS m/z: 423 (M+H)+.