Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>C(O)C>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([NH:13][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccn(Cc2ccccc2)n1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccn(Cc2ccccc2)n1)C(=O)OCC

Procedure:
1-benzyl-3-amino-pyrazole, m.p. 57°-59° C. (4 g) was reacted with diethyl ethoxymethylenemalonate (6 g) in anhydrous ethanol (40 ml) at the reflux temperature for 3 hours. After cooling the solution was evaporated in vacuo to dryness. Crystallization obtained by dilution with hexane gave diethyl N-(1-benzyl-pyrazol-3-yl)-aminomethylenemalonate, m.p. 60°-62° C. (7.5 g), which was reacted with polyphosphoric acid (3.2 g: 1.5 g of P2O5 and 1.7 g of H3PO4) and POCl3 (13.5 g) under stirring at 120° C. for 30 minutes. After cooling the reaction mixture was diluted with ice water: neutralization with 35% NaOH gave a precipitate which was filtered and washed with water. Crystallization from methanol gave 6 g of 1-benzyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid, ethyl ester, m.p. 172°-173° C., which was hydrolized by heating with a mixture 1:1 of 37% HCl:acetic acid (300 ml) at the reflux temperature for 4 hours. After cooling the reaction mixture was neutralized to pH=6 with 35% NaOH and the precipitate was filtered and washed with water: crystallization from isopropyl alcohol gave 9.7 g of 1-benzyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid, m.p. 198°-199° C.
Reaction SMILES: [CH:1]([C:3]1([CH2:26][CH2:27][CH3:28])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=O.O.NN.[OH-].[K+]>C(O)COCCO>[CH3:1][C:3]1([CH2:26][CH2:27][CH3:28])[CH2:4][CH2:5][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1
Reactant: CCCCCc1ccc(-c2ccc(C3CCC(C=O)(CCC)CC3)cc2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCCc1ccc(-c2ccc(C3CCC(C)(CCC)CC3)cc2)cc1
Reaction time: 12 h

Procedure:
A mixture of 3.7 g (0.01 mole) of 4-(4-formyl-4-propylcyclohexyl)-4'-pentylbiphenyl (Example 2), 40 ml of diethylene glycol, 15 ml of 90% hydrazine hydrate and 5.5 g of potassium hydroxide is heated and the hydrazine and water are distilled off until the temperature has risen to about 230° C. The reaction mixture is then boiled for 12 hours and, when cold, 200 ml of water are subsequently added. After customary working up, 4-(4-methyl-4-propylcyclohexyl)-4'-pentylbiphenyl is obtained.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.[O:27]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:1][CH2:2][OH:27])[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
A solution of (R)-6-allyl-3-((R)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (334 mg, 0.80 mmol) in dry CH2Cl2 (20 mL) was treated with ozone at −78° C. until the reaction mixture became blue. Then the mixture was flushed with oxygen to remove excess ozone. To the above mixture was added NaBH4 (273 mg, 7 mmol) at 0° C. and the reaction mixture was stirred for 4 hrs at ambient temperature under nitrogen. The reaction mixture was washed with water and then extract with CH2Cl2 twice. The combined organic phases were dried over NaSO4, filtered and concentrated to give the residue, which was purified by preparative HPLC to afford (S)-3-((R)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (118 mg, 35%). 1H NMR (CD3OD): 1.50 (m, 3H), 2.12 (m, 2H), 2.29 (m, 2H), 2.50 (m, 1H), 3.10 (m, 1H), 3.33 (m, 1H), 3.68 (m, 1H), 4.56 (m, 1H), 5.50 (m, 1H), 6.86 (m, 2H), 7.10 (m, 2H), 7.30 (m, 4H).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2([CH3:46])[O:45][CH2:44][CH2:43][O:42]2)=[CH:37][C:36]=1[S:47]([NH2:50])(=[O:49])=[O:48]>CC#N>[Br:1][CH2:46][C:41]1([C:38]2[CH:39]=[CH:40][C:35]([F:34])=[C:36]([S:47]([NH2:50])(=[O:49])=[O:48])[CH:37]=2)[O:45][CH2:44][CH2:43][O:42]1
Reactant: CC1(c2ccc(F)c(S(N)(=O)=O)c2)OCCO1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: CC#N
Product: NS(=O)(=O)c1cc(C2(CBr)OCCO2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A solution of 8.4 g (0.0225 mole) of phenyltrimethylammonium tribromide in 20 mL of CH3CN was added dropwise to a solution of 5.2 g (0.022 mole) 2-fluoro-5(2-methyl-[1,3]dioxolan-2-yl)-benzenesulfonamide III in 100 mL of CH3CN. The reaction was stirred at room temperature for 1 hr. The solvent was evaporated in vacuo. The residue was dissolved in EtOAc, washed with water, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with CH2Cl2/Et2O::9/1 to give 4.6 g of IV (62%) as an oil. CH2Cl2/Et2O::9/1 single-spot material Rƒ 0.30.1H NMR (300 MHz CDCl3) δ: (3.68, s, 2H), (3.80,m , 2H), (4.21, m, 2H), 5.15, broad s, 2H), (7.26, t, 1H), (7.75, m, 1H), 8.15, dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[Cl-].[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH2+:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].C([O-])(=O)C.[Na+].C(OC)(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CC[NH2+]CC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)N1CCNCC1
Solvent: COC(OC)OC
Solvent: ClCCCl
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C

Procedure:
Scheme 7 shows the synthesis of 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine 20 by formylation of 4-(2-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine 18 in THF at −78° C. with n-BuLi in hexanes (1.2 equiv.). The resulting slurry was allowed to warm up to −60° C., cooled to −78° C. and DMF (1.5 equiv.) was added slowly to afford 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde 19. To a suspension of 19, 4-(methylsulfonyl)piperazin-1-ium chloride 8 (alternatively named as 1-(methylsulfonyl)piperazine hydrochloride, 1.45 equiv.) and anhydrous sodium acetate in 1,2-dichloroethane was added trimethyl orthoformate (10 equiv.). The slurry was stirred at ambient temperature for at least 6 hours, then sodium triacetoxyborohydride was added and the reaction was stirred for 24 hours to give 20.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]([NH2:10])=[C:8]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18]CC3C=CC=CC=3)[C:12]=2[O:26][CH3:27])[C:7]([CH3:28])=[N:6]1)([CH3:4])[CH3:3].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>C1COCC1.C(OCC)(=O)C.[Pd]>[NH2:10][C:9]1[N:5]([C:2]([CH3:3])([CH3:4])[CH3:1])[N:6]=[C:7]([CH3:28])[C:8]=1[C:11]1[C:12]([O:26][CH3:27])=[C:13]([OH:18])[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: COc1c(OCc2ccccc2)cc(F)cc1-c1c(C)nn(C(C)(C)C)c1N
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(O)cc(F)cc1-c1c(C)nn(C(C)(C)C)c1N
Yield: 93.1 %

Procedure:
A solution of 1-(1,1-dimethylethyl)-4-(5-fluoro-2-(methyloxy)-3-[{phenylmethyl)oxy]phenyl}-3-methyl-1H-pyrazol-5-amine (25 g, 0.0652 mol) in a mixture of THF-ethyl acetate (1:1, 300 mL) was hydrogenated over 10% Pd—C (2.5 g) at 40 Psi for 2 h. The catalyst was filtered off, and the filtrate was concentrated. The resulting crude was triturated with diethyl ether; a white solid was precipitated. It was collected by filtration, washed with an additional portion of diethyl ether and dried in vacuo to give 17.8 g of 3-[5-amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]-5-fluoro-2-(methyloxy)phenol (93%). 1H NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 6.56 (dd, 1H), 6.38 (dd, 1H), 4.44 (s, 2H), 3.37 (s, 3H), 1.98 (s, 3H), 1.56 (s, 9H); MS (EI) for C15H20FN3O2: 294 (MH+)
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCCN1CCC(O)CC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: O=[N+]([O-])c1ccccc1OCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethylbromide and 4-hydroxy-1-[4-(2-nitrophenoxy)butyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy-1-[4-(2-nitrophenoxy)butyl]piperidine.
Reaction SMILES: CO.[BH4-].[Na+].[N+:5]([N:8]1[C:12]2=[C:13]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:14]3[CH:15]=[CH:16][C:17]([N:52]=3)=[C:18]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:19]3[N:23]([N+:24]([O-])=O)[C:22]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[C:28]4[N:39]=[C:31]([C:32]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[C:9]1[CH:10]=[CH:11]2)[CH:30]=[CH:29]4)=[CH:21][CH:20]=3)([O-])=O>[Pd].ClCCl>[NH2:24][N:23]1[C:19]2=[C:18]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:17]3[CH:16]=[CH:15][C:14]([N:52]=3)=[C:13]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:12]3[N:8]([NH2:5])[C:9]([C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:31]4[N:39]=[C:28]([C:27]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)=[C:22]1[CH:21]=[CH:20]2)[CH:29]=[CH:30]4)=[CH:10][CH:11]=3
Reactant: O=[N+]([O-])n1c2ccc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc(c(-c4ccccc4)c4nc(c2-c2ccccc2)C=C4)n3[N+](=O)[O-])C=C1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nn1c2ccc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc(c(-c4ccccc4)c4nc(c2-c2ccccc2)C=C4)n3N)C=C1
Yield: 96.2 %

Procedure:
A 2-1 three-necked round bottomed flask was fitted with a condenser and a dropping funnel to add solid material. To this flask was added anhydrous dichloromethane (850-ml) and methanol (420-ml). To this organic solution was added 10% palladium on carbon (14.0 g), the mixture was stirred under an argon blanket, and then cooled in an ice bath. Sodium borohydride (4.0 g, mol) was added in small portions over about 30-min. Next the dinitrotetraphenylporphyrin (7.0 g, 0.01 mol) and solid sodium borohydride (14.0 g) were added in small portions over about 60-min. The reaction mixture was stirred under argon for 30 min. The reaction mixture was filtered through a layer of CELITE® (diatomateous earth of Johns Manville, Denver, Colo.) in a Buchner funnel and washed repeatedly with dichloromethane. The solvent was completely removed under reduced pressure to produce a crude residue. The residue was redissolved in dry dichloromethane to separate insoluble CELITE®, and filtered. The solvent was removed under reduced pressure and dried to produce a purified residue (6.2 g). This residue was flash chromatographed over silica using dichloromethane as eluent. The product obtained (0.6 g, 9.6% yield) was free of impurities. See FIG. 4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[I-].[N:18]1([C:28](N2C=C[N+](C)=C2)=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:28]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[O:29])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Agent: [I-]
Product: O=C(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)N1CCCc2ccccc21

Procedure:
The title compound was prepared from 4-(3,5-dichloro-pyridin-2-yloxy)-phenol and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was recrystallized (ethanol) (68%). HPLC-MS m/z=415.2 (M+1), Rt: 5.6 min.
Reaction SMILES: N1C(F)=NC(F)=NC=1F.N[C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14](C2C(C)=C(S(O)(=O)=O)C(C)=C(N)C=2C)=[CH:13][C:12]=1[S:41]([OH:44])(=[O:43])=[O:42].P([O-])([O-])(O)=O.[Na+].[Na+].[OH-].[Na+].C(N)CN>O>[CH:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[S:41]([OH:44])(=[O:43])=[O:42]
Reactant: Cc1c(N)c(C)c(S(=O)(=O)O)c(C)c1-c1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Agent: Fc1nc(F)nc(F)n1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: NCCN
Solvent: O
Product: O=C1c2ccccc2C(=O)c2cc(S(=O)(=O)O)ccc21

Procedure:
The compound can be prepared as follows: 14 parts of cyanuric fluoride are added dropwise to a neutral solution of 53 parts of 1-amino-4-(3-amino-2,4,6-trimethyl-5-sulfophenyl)anthraquinone-2-sulfonic acid and 5 parts of disodium hydrogenphosphate in 500 parts of water at a temperature below 2° C., while keeping the pH constant by the addition of sodium hydroxide solution. Upon completion of the reaction,a solution of 6 parts of ethylenediamine in 54 parts of water are added dropwise such that the temperature does not exceed 5 and the pH remains at6. The pH is then kept at 6. A solution of 1-amino-4-{3-[4-(2-amino-ethylamino)-6-fluoro-[1,3,5]-triazin-2-ylamino]-2,4,6-trimethyl-5-sulfophenyl)}-anthraquinone-2-sulfonic acid (solution 1) is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:34]1([CH2:39][CH2:40][CH2:41]O)[CH2:38][CH2:37][CH2:36][CH2:35]1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:41][CH2:40][CH2:39][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: OCCCN1CCCC1
Reactant: COc1cc2c(Cl)cnnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)cnnc2cc1OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.5 %

Procedure:
To a solution of 4-chloro-7-hydroxy-6-methoxycinnoline (300 mg, 1.42 mmol), triphenylphosphine (747 mg, 2.85 mmol) and 3-(pyrrolidin-1-yl)propan-1-ol (276 mg, 2.1 mmol) in methylene chloride (12 ml) was added diethyl azodicarboxylate (449 μl, 2.85 mmol) dropwise and the mixture was stirred for 2 hours at ambient temperature. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol (90/10) followed by methylene chloride/methanol/methanol saturated with ammonia (89/10/1 followed by 85/10/5). The fractions containing the expected product were combined and evaporated to give 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (80 mg, 18%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].C(O)C.Cl.[OH-].[Na+]>[Fe].O>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([O:11][CH3:12])=[C:2]([Br:1])[CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1Br

Procedure:
To a mixture of 2-bromo-4-nitroanisole (5.0 g, 21.5 mmol, Lancaster), ethanol (25 mL) and water (25 mL), was added powdered iron (4.8 g, 86 mmol) and 12 N HCl (0.5 mL). The solution was heated at reflux for 20 minutes. 1N NaOH (10 mL) was added and the reaction mixture was filtered through a pad of celite while still hot, and then rinsed with ethanol (2×50 mL). The ethanol was removed under reduced pressure and the residue extracted with dichloromethane (2×100 mL). The organic extracts were dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography on silica gel (75 g) eluting with dichloromethane, to give 4-amino-2-bromoanisole as a light tan solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O.C(C1C=CC=C2C=1NC=C2)(=O)C1C=CC=CC=1.C(Cl)Cl>C(Cl)Cl>[C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[Cl:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccc2cc[nH]c12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cccc2c(Cl)c[nH]c12
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
The 7-benzoylindole product (approximately 0.87 mole) in methylene chloride (the reaction mixture obtained in Example 2) is agitated and chilled to 15° C. in a nitrogen atmosphere. N-Chlorosuccinimide (0.87 mole) (NCS) is divided into four equal portions and added to the 7-benzoylindole-methylene chloride mixture at one-half hour intervals while maintaining the reaction temperature between 15°-20° C. One hour after the addition of the final portion of N-chlorosuccinimide, the succinimide is washed from the reaction by adding approximately 2.5 liters of water to the reaction mixture, agitating for about 15 minutes and then allowing the resulting layers to separate. The lower methylene chloride layer is drawn into another vessel and washed again with about 2.5 liters of water. The two aqueous portions are combined and extracted with about 0.2 liters of methylene chloride. This methylene chloride solution is washed with an equal volume of water. The two methylene chloride solutions are combined and distilled at a reduced pressure to a liquid temperature of approximately 80° C. The 7-benzoyl-3-chloro-indole residue obtained has a melting range of 145°-149° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][Mg]Br>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([OH:13])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC1(O)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 36.8 %

Procedure:
3-Oxo-pyrrolidine-1-carboxylic acid tert-butyl ester [Hofmann, J. Agric. Food Chem., 46, 3902 (1998)] (0.322 g, 1.74 mmol) was dissolved in diethyl ether (5 ml), cooled with an ice bath, and treated with methylmagnesium bromide (3M in ether, 0.64 ml, 1.91 mmol). The reaction was stirred for 1 h then more methylmagnesium bromide added, and the mixture stirred for 63 h. The reaction was quenched with aqueous ammonium chloride and extracted with diethyl ether (×3). The combined organic extracts were dried and evaporated. The residue was purified by flash chromatography, eluting with 0–50% ethyl acetate in petroleum ether, to give the title compound as a sticky off-white solid (0.129 g, 37%); NMR (CDCl3) 1.41 (3H, s), 1.46 (9H, s), 1.61 (1H, s), 1.79–1.92 (2H, m), and 3.17–3.58 (4H, m).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]#[N:24])=[O:17].C(N(CC)CC)C>ClCCl>[OH:13][CH:4]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][NH:2][CH2:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]#[N:24])=[O:17]
Reactant: N#CC1CCCN1C(=O)CCl
Reactant: NCC(O)COc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC1CCCN1C(=O)CNCC(O)COc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
A solution of 1-amino-3-phenoxypropan-2-ol hydrochloride (7.9 g, 38.8 mmol) and 1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (6.1 g, 35.3 mmol) in DCM (250 mL) was added triethylamine (15 mL, 106 mmol). The mixture was stirred at room temperature overnight. After the TLC showed that the reaction was complete, the mixture was washed by brine. The aqueous solution was extracted with dichloromethane (DCM) (3×100 mL) and the combined DCM solution was concentrated to give a crude product, which was purified by column chromatography to give 3.5 g of 1-(2-(2-hydroxy-3-phenoxypropylamino)acetyl)pyrrolidine-2-carbonitrile (as shown at 6). Yield was 33.6%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.[Cu]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:14]=2[C:15]#[N:16])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(C)c1ccc(N)c(C#N)c1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(Nc2ccc(Cl)cc2[N+](=O)[O-])c(C#N)c1
Temperature: 160 °C
Yield: 37.5 %

Procedure:
Combine 1,4-dichloro-2-nitro-benzene (0.513 g, 2.67 mmol), 2-amino-5-isopropyl-benzonitrile (0.514 g, 3.21 mmol), potassium carbonate (0.754 g, 5.45 mmol), and fine granular copper (0.031 g, 0.48 mmol) in dimethylformamide (5 ml). Heat the reaction mixture to 160° C. for 16 hours, and cool to ambient temperature. Dilute the reaction mixture with 50 ml of ethyl acetate and wash 3 times with 50 ml water and once with 50 ml of brine. Collect organic layer, dry over sodium sulfate and evaporate solvent. Purify the residue via flash chromatography eluting with a step gradient starting with 90% hexanes: 10% ethyl acetate and going to 85% hexanes: 15% ethyl acetate to obtain 0.316 g (1.00 mmol, 37% yield) of the title compound as an orange amorphous solid: Mass Spectrum (m/e): 316 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][CH:22]([CH:26]1[CH2:28][CH2:27]1)[C:23]([NH2:25])=[O:24].CO>CCCCCCC>[C:23]([CH:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH:26]1[CH2:28][CH2:27]1)(=[O:24])[NH2:25]
Reactant: NC(=O)C(N)C1CC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Solvent: CO
Solvent: CCCCCCC
Product: NC(=O)C(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethyloxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69b) and α-amino-cyclopropaneacetamide (CAN 1100749-41-4) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/40% ethanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 381.1739 (M+H)+, αD20 (MeOH)=+35.0°.