Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7](C)[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:27]([C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[CH3:38])#[N:28]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:32]4[CH:31]=[C:30]([CH3:38])[C:29]([C:27]#[N:28])=[N:34][CH:33]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: Cc1cc(B(O)O)cnc1C#N
Product: Cc1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)CC3)cnc1C#N

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and (6-cyano-5-methylpyridin-3-yl)boronic acid (Combi-Blocks, Cat. No. PN-5814). LCMS (M+H)+: m/z=441.1.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:14]=[O:15])[C:10](=[O:16])[N:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.[O-:23]Cl=O.[Na+]>C(O)CCC>[CH3:1][N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:15])=[O:23])[C:10](=[O:16])[N:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [O-][Cl+][O-]
Reactant: Cc1c(C=O)c(=O)n(-c2ccccc2)n1Cc1ccccc1
Agent: [Na+]
Solvent: CCCCO
Product: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.3 %

Procedure:
To a mixture of 1-benzyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxaldehyde (1 g, 4.624 mmol) in butyl alcohol were added to NaClO2 (1.254 g, 13.873 mmol) in an aqueous solution and potassium phosphate monobasic monohydrate (3.146 g, 23.12 mmol) in an aqueous solution slowly at 0° C. The resulting reaction mixture was slowly heated to room temperature and stirred for 10 hours. NaClO3 (1 g) was further added while monitoring the reaction. Following the addition of sodium chlorite, the reaction mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with, dried with Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was washed with 20% ethyl acetate solution in small amount of hexane. The target compound was obtained as a white solid (808 mg, 3.48 mmol, 75% yield).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH:15]([CH3:26])[CH2:16][N:17]2[CH2:22][CH2:21][CH:20]=[C:19]([CH2:23][O:24][CH3:25])[CH2:18]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>C(O)C.[C].[Pd]>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH:15]([CH3:26])[CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][O:24][CH3:25])[CH2:18]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC1=CCCN(CC(C)Cc2cccc(Oc3ccccc3)c2)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COCC1CCCN(CC(C)Cc2cccc(Oc3ccccc3)c2)C1
Yield: 94.5 %

Procedure:
N-[3-(m-Phenoxyphenyl)-2-methylpropyl]-3-methoxymethyl-1,2,5,6-tetrahydropyridine (0.2 g) was dissolved in ethanol (20 ml), followed by addition of acetic acid (1 ml) thereto. To the resultant mixture, 5% palladium-carbon (0.2 g) was added at room temperature under nitrogen stream, and then hydrogenation was carried out under nitrogen stream. After absorption of hydrogen was completed, the catalyst was removed by filtration, and the filtrate was combined with 15% aqueous sodium hydroxide solution (20 ml) and extracted with diethyl ether. The ether extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give N-[3-(m-phenoxyphenyl)-2-methylpropyl]-3-methoxymethylpiperidine (0.19 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][C:24](=[O:26])[N:23]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)[C:22]1=[O:35])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C@@:25]2([CH2:11][CH2:10][CH2:9][C@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:24](=[O:26])[N:23]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)[C:22]1=[O:35])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Reactant: BrCCCC(Br)c1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(Br)cc1

Procedure:
Using the same procedure as in Example 1 starting from 1-bromo-4-(1,4-dibromobutyl)benzene (153 mg, 0.4 mmol) (Preparation 4) and 3-(3,5-dichlorophenyl)-2,4-dioxoimidazolidine-1-carboxylic acid tert-butyl ester (113 mg, 0.33 mmol) (Preparation 11), the above-titled compound was obtained (33 mg) as a white solid. 1H NMR (CDCl3): 7.48 (2H, d, J=8.3 Hz), 7.30 (1H, m), 7.07 (2H, d, J=8.3 Hz ), 6.52 (2H, m), 4.06 (1H, dd, J1=13.1 Hz, J2=5.5 Hz), 2.35-2.6 (3H, m), 2-2.35 (3H, m), 1.66 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(Br)cc(OC)c1
Solvent: CC(=O)OC(C)=O
Product: COc1cc(Br)cc(OC)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 25.2 %

Procedure:
1-Bromo-3,5-dimethoxybenzene (10.9 g, 50 mmol) was dissolved in 100 mL of acetic anhydride and cooled to 0° C. A cooled solution of 70% HNO3 (6.4 mL, 100 mmol) in 20 mL of acetic anhydride was added dropwise and the resulting mixture was stirred for 1 hour at 0° C. and for 3 hours at room temperature. The reaction mixture was poured into ice-water with strong stirring and the yellow solid was filtered and washed with water. The solid as a mixture of two isomers was separated by silica gel column (ISCO, hexane/EtOAc, 0-30%, 40 min) to give 3.3 g (25%) of pure 5-bromo-1,3-dimethoxy-2-nitro-benzene as an yellow solid. 1H-NMR (DMSO-d6, 400 MHz): δ 7.17 (s, 2H), 3.89 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].C(N(CC)CC)C.[C:38]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)#[N:39]>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:44](=[O:45])[C:43]4[CH:47]=[CH:48][C:40]([C:38]#[N:39])=[CH:41][CH:42]=4)[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Oc1cc(-c2cn(C3CCN(C(=O)c4ccc(C#N)cc4)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h

Procedure:
The product of the above mentioned Example 2 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) was added to N,N-dimethyl formamide (10 mL), triethylamine (404 mg, 4 mmol) and p-cyanobenzoyl chloride (496.5 mg, 3 mmol) were added, and the reaction was performed overnight at room temperature. The resultant mixture was washed with water for several times, dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane/methanol=15:1) to yield the target product as white solid powder.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](O)=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21].CN.C1C=CC2N(O)N=[N:30][C:28]=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:30][CH3:28])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: O=C(O)c1c(-c2ccc(Br)cc2)oc2ccc(O)c(F)c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(Br)cc2)oc2ccc(O)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-fluoro-2-(4-bromophenyl)-5-hydroxybenzofuran-3-carboxylic acid (0.62 g, 1.77=10, 1 eq), 2M solution of methylamine in THF (5.4 ml, 10.8 mmol, 6.1 eq), HOBT (0.43 g, 3.18 mmol, 1.8 eq), EDCI.HCl (0.61 g, 3.18 mmol, 1.8 eq) in THF at r.t. under an nitrogen atmosphere was added diisopropylethylamine (1.9 ml, 10.9 mmol, 6.2 eq). The clear reaction mixture was stirred at r.t. overnight. The reaction mixture was concentrated and diluted with water, and then the solid precipitate was collected by filtration. The product was washed with petroleum ether and dried under vacuum. Yield: 0.51 g (79.7%). 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.63 (t, J=4.4 Hz, 1H), 7.79-7.72 (m, 4H), 7.33 (d, J=8.8 Hz, 1H), 7.02 (m, 1H), 2.81 (d, J=4.4 Hz, 3H).
Reaction SMILES: C(N)(C)C.CC1(C)[NH:11][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([O:17][CH2:18][CH:19]([NH:21][CH2:22][CH:23]([OH:36])[CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:35])[NH:33][CH3:34])=[CH:28][CH:27]=3)[CH3:20])[CH:15]=[CH:16][C:8]=2[O:7]1>CO>[C:10]([C:9]1[CH:13]=[C:14]([CH:15]=[CH:16][C:8]=1[OH:7])[O:17][CH2:18][CH:19]([NH:21][CH2:22][CH:23]([OH:36])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:35])[NH:33][CH3:34])=[CH:28][CH:27]=1)[CH3:20])(=[O:12])[NH2:11]
Reactant: CNC(=O)c1ccc(OCC(O)CNC(C)COc2ccc3c(c2)C(=O)NC(C)(C)O3)cc1
Solvent: CC(C)N
Solvent: CO
Product: CNC(=O)c1ccc(OCC(O)CNC(C)COc2ccc(O)c(C(N)=O)c2)cc1

Procedure:
80 ml of isopropylamine are added to a solution of 18.0 g of crude 1-[2-(2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-6-yloxy)-1-methylethylamino]-3-(4-methylcarbamoylphenoxy)propan-2-ol in 300 ml of methanol and the solution is refluxed for 1 hour. The reaction mixture is concentrated by evaporation and the oil remaining is crystallised from 80 ml of isopropanol. 1-[2-(3-Carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-(4-methylcarbamoylphenoxy)propan-2-ol having a melting point of 172°-175° (diastereoisomeric mixture) is obtained.
Reaction SMILES: C[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[CH2:10][O:11]C(C)=O>>[CH3:10][O:11][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: CCOC(C)=O
Product: COc1ccc(N)cc1

Procedure:
Column chromatography was performed in the dark, using 50% EtOAc/50% hexanes as eluent. Three bands emerged; the first band was a fluorescent impurity, the second and third bands were the di-(rf˜0.7) and monomethyl aniline (rf˜0.65), respectively. Rotary evaporation of the middle fractions gave the product in modest yield (˜1 gram, 16% based on starting p-anisidine). The off-white solid was further purified by sublimation (high vacuum, heated at 30° C., collected on a small cold finger). Product isolated at this stage was sufficiently pure for reductive quenching purposes. Due to its short shelf-life (stored at 4° C., under argon, protected from light), the compound was frequently recrystallized from warm water before use. 1H NMR (CDCl3): δ 3.30 (s, N—CH3, 6H), 3.88 (s, O—CH3, 3H), 7.58 (d, 21), 7.15 (d, 21). GC-MS calcd for C9H13NO (M−H+) m/z 150, found 150.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9](=[NH:12])[NH:10][OH:11])[CH:6]=[CH:5][C:4]=1[NH:13][C:14](=[O:16])[CH3:15])[CH3:2].[CH2:17]([N:19]([CH2:30][CH3:31])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([CH3:29])[N:28]=1)[C:23](O)=O)[CH3:18]>>[CH2:30]([N:19]([CH2:17][CH3:18])[C:20]1[CH:21]=[C:22]([C:23]2[O:11][N:10]=[C:9]([C:7]3[CH:6]=[CH:5][C:4]([NH:13][C:14](=[O:16])[CH3:15])=[C:3]([CH2:1][CH3:2])[CH:8]=3)[N:12]=2)[CH:26]=[C:27]([CH3:29])[N:28]=1)[CH3:31]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: CCc1cc(C(=N)NO)ccc1NC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)ccc1NC(C)=O

Procedure:
The title compound is prepared in analogy to Example 5 starting from N-[2-ethyl-4-(N-hydroxycarbamimidoyl)-phenyl]-acetamide and 2-diethylamino-6-methyl-isonicotinic acid; LC-MS: tR=0.81 min, [M+1]+=394.15; 1H NMR (CDCl3): δ 1.25 (t, J=7.0 Hz, 6H), 1.36 (t, J=7.3 Hz, 3H), 2.28 (s, 3H), 2.50 (s, 3H), 2.73 (q, J=7.3 Hz, 2H), 3.63 (q, J=6.8 Hz, 4H), 7.01 (s, 1H), 7.08-7.16 (m, 2H), 8.03-8.09 (m, 2H), 8.13-8.21 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[Cl:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[Cl:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: OB(O)c1cccc(F)c1Cl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccc(F)c1Cl

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-chloro-3-fluoro-benzeneboronic acid (CAS RN 871329-52-1) and using preparative HPLC for the chromatographic purification. Off-white sticky solid (36%). MS (ESI): m/z=477.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][N:14](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1)#[N:14]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C#N)cc1C
Temperature: 140 °C
Yield: 26 %

Procedure:
A mixture of methyl 4-bromo-2-methylbenzoate (1 g, 4.4 mmol), zinc cyanide (0.7 g, 6.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.086 mmol) in N,N-dimethylformamide was heated to 140° C. under nitrogen atmosphere. And then the mixture stirred under reflux condition for 12 hours. The mixture was cooled to room temperature, and partitioned between dichloromethane (20 mL*3) and brine (60 mL). The organic layer was concentrated to dryness and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=15:1) to give methyl 4-cyano-2-methylbenzoate as a white solid (200 mg, 26%). LRMS (M+H+) m/z: calcd 175.06. found 175. 1H NMR (300 MHz, CDCl3): δ 7.97 (d, J=8.7 Hz, 1H), 7.57-7.53 (m, 2H), 3.93 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH2:18][CH2:19]O)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([F:22])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:21][CH2:19][CH2:18][N:10]([C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:9]2)=[C:4]([F:22])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)c1ccc(Br)cc1F
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a stirred solution of (RS)-tert-butyl 2-(4-bromo-2-fluorophenyl)-2-hydroxyethyl(2-hydroxyethyl)carbamate (15.5 g) and triethylamine (9.85 ml) in THF (120 ml) at 0-5° C. was added dropwise methanesulfonyl chloride (3.35 ml). The reaction mixture was then stirred at room temperature for 1 hour to afford a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (20 ml). The filtrate was cooled to 0-5° C. and potassium 2-methyl-2-butoxide (36.2 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 20 min and then poured into EtOAc and washed sequentially with 1 M aq. HCl, water and saturated brine. The organic phase was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford (RS)-tert-butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate (6.46 g, 44%) as a yellow oil. MS (EI): 305 ([{81Br}M-C4H8]+), 303 ([{79Br}M-C4H8]+), 260 ([{∥Br}M-C4H8—CO2H]+), 258 ([{79Br}M-C4H8—CO2H]+).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:15]=[C:14]3[C:10]([C:11]([C:16]([OH:18])=[O:17])=[N:12][NH:13]3)=[CH:9][CH:8]=2)=[N:4][CH:3]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:15]=[C:14]3[C:10]([C:11]([C:16]([O:18][C@H:21]4[CH:22]5[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]5)[CH2:20]4)=[O:17])=[N:12][NH:13]3)=[CH:9][CH:8]=2)=[N:4][CH:3]=1
Reactant: Cc1cnc(-c2ccc3c(C(=O)O)n[nH]c3c2)s1
Reactant: O[C@H]1CN2CCC1CC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccc3c(C(=O)O[C@@H]4CN5CCC4CC5)n[nH]c3c2)s1
Temperature: 25 °C
Yield: 1 %

Procedure:
To a solution of 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid (0.50 mmol), (3R)-quinuclidin-3-ol (0.57 mmol), and triphenylphosphine (0.57 mmol) in tetrahydrofuran (5 mL) at 0° C. was added a solution of diisopropyl azodicarboxylate (0.57 mmol) in tetrahydrofuran (1 mL). The mixture was allowed to warm to rt over 2 hours and was maintained for 16 h. The mixture was loaded on a SCX column (5 g) and was washed with methanol. Product was eluted with methanol/dimethylethylamine (9/1) and concentrated. The residue was purified by preparative HPLC to produce the desired product in 1% yield. 1H NMR (CD3OD) δ 8.65 (s, 1 H), 8.51 (s, 1 H), 8.04 (d, J=6.0, 1H), 7.74 (d, J=6.0, 1 H), 7.55 (s, 1 H), 5.45 (m, 1 H), 3.81 (m, 1 H), 3.45-3.20 (m, 5H), 2.55 (s, 3 H), 2.55 (m, 1 H), 2.36 (m, 1 H), 2.21-1.93 (m, 3 H); LC/MS (EI) tR 4.7 min, m/z 369 (M++1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(Br)n1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(Br)n1
Temperature: 25 °C

Procedure:
10 g (53.8 mmol) of 6-bromo-pyridine-2-carbaldehyde were dissolved in 70 ml of pyridine and 6.73 g (64.5 mmol) of malonic acid and 457 mg (5.4 mmol) of piperidine were added. The reaction mixture was boiled under reflux for 6 h. The solution was cooled to room temperature and then poured onto ice. Concentrated hydrochloric acid was added until pH=5, whereupon the product precipitated. The product was isolated by filtration and dried under reduced pressure. Yield: 9.85 g.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6]N[CH2:8]2.[C:17]([BH3-])#[N:18].[Na+]>CO.O>[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][N:18]([CH2:17][CH2:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:3]=1)[CH2:8]2
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(CCc1ccccc1)CC2
Reaction time: 1 h
Yield: 190.3 %

Procedure:
A solution of the product from Example 5 (1 g, 3.24 mmol) and phenylacetylaldehyde (0.82 ml, 7 mmol) in 2:1 MeOH/H2O (50 mL) was treated with sodium cyanoborohydride (0.56 g, 9 mmol) portionwise under nitrogen and stirred for one hour. The reaction mixture was then cooled under an ice bath and precipitate filtered off. The solids were washed with hexane and oven dried to give the title compound (1.16 g, 95% yield) as an orange solid, mp=120-122° C.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C([O:14][C:15](=O)[CH2:16][C:17]([CH3:19])=O)C>>[O:14]=[C:15]1[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=[C:17]([CH3:19])[CH2:16]1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccc(C(=O)O)cc1
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1

Procedure:
From the reaction of 4-hydrazinobenzoic acid and ethylacetoacetate, 4-(4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl)-benzoic acid is obtained. Subsequent reaction with 2-ethylaniline yeilds 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl)-benzoic acid, Mp 291° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: COc1cccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c1
Yield: 67 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 3-methoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=80:20 to 20:80, 205 mg, 67%) which was obtained as a white solid. MS: m/e=334.1 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])([CH3:3])[CH3:2].C([Li])CCC.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.C(OCC)(=O)C.Cl>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:32])=[O:31])[CH:9]=[C:8]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)Oc1ccc2[nH]cc(CCC(=O)O)c2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of propionic acid (27) (96.3mg, 0.510 mmol) in tetrahydrofuran (10 ml), n-butyl lithium (1.40 ml, 2.24 mol) was added next and stirred for 30 minutes at −78° C. Benzene sulfonyl chloride (277 mg, 1.5 mmol) was added next, and the reaction was stirred for 16-24 hours, allowing temperature to rise from −78° C. to ambient conditions. The reaction was then diluted with ethyl acetate, and 1M HCl was added to adjust the pH to 1-2. The layers were then separated, and the organic layer was placed over magnesium sulfate and concentrated under reduced pressure. The crude material was then purified by flash chromatography with silica, eluting with 5% methanol in dichloromethane to yield the desire product (22) as a white solid. (M−1=386.4)
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.NN>[Ni].C(O)C>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)CCCn1c(-c2ccccc2)cc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)CCCn1c(-c2ccccc2)cc2cc(N)ccc21

Procedure:
While stirring, 32.3 g (0.1 mol) of 1-(3'-dimethylamino-propyl)-2-phenyl-5-nitro-indole, prepared as in Example 1, was mixed with 15 g (0.3 mol) of hydrazine hydrate, 300 ml of pure absolute ethanol and a small quantity of Raney Nickel.