Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)([CH3:15])[CH2:3][NH:4][C:5]1([C:11](OC)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CC(O)=O.C([O-])(O)=O.[Na+]>>[F:23][C:18]1[CH:17]=[C:16]([C@@:2]2([CH3:15])[NH:1][C:11](=[O:12])[C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[NH:4][CH2:3]2)[CH:21]=[C:20]([F:22])[CH:19]=1
Reactant: COC(=O)C1(NCC(C)(N)c2cc(F)cc(F)c2)CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@]1(c2cc(F)cc(F)c2)CNC2(CCCCC2)C(=O)N1

Procedure:
A solution of methyl 1-{[2-amino-2-(3,5-difluorophenyl)propyl]amino}cyclohexanecarboxylate from Step F (205 mg, 0.628 mmol), and AcOH (0.36 mL, 6.28 mmol) in xylenes (5 mL) was heated at 80° C. for 3 h, allowed to cool, then poured into saturated aqueous NaHCO3 (5 mL). The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of EtOAc:MeOH-100:0 to 92:8, to give the racemic product. The enantiomers were separated by HPLC, using a ChiralPak AD column and eluting with hexane:EtOH:Et2NH-40:60:0.1. The first major peak to elute was (3R)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one, the title compound, and the second major peak to elute was (3S)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:25][CH3:26])=[C:8]([CH:24]=1)[C:9]([NH:11][CH:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17]([CH3:23])=[CH:18][CH:19]=2)[O:14][CH2:13]1)=[O:10].Cl>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:25][CH3:26])=[C:8]([CH:24]=1)[C:9]([NH:11][CH:12]1[CH:21]([OH:22])[C:20]2[C:15](=[CH:16][C:17]([CH3:23])=[CH:18][CH:19]=2)[O:14][CH2:13]1)=[O:10]
Reactant: COc1ccc(Cl)cc1C(=O)NC1COc2cc(C)ccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cl)cc1C(=O)NC1COc2cc(C)ccc2C1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.5 g (12.5 mmol) of sodium borohydride was introduced into a suspension of 8.65 g (25 mmol) of 3-(5-chloro-2-methoxybenzamido)-7-methyl-4-chromanone in 40 ml of ethanol. During stirring at 30°-40° C. for 2 hours, the solid dissolved. The solution was then cooled, introduced into ice/water and acidified to pH 1-2 with dilute hydrochloric acid. The precipitate was filtered off with suction, washed with water, dried and recrystallized from ethanol. The resulting 3-(5-chloro-2-methoxybenzamido)-7-methylchroman-4-ol (diastereomer mixture) had a melting point of 151°-152° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[O:7][C@H:8]([CH2:10][OH:11])[CH2:9][C@@H:4]2[O:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[O:7][C@H:8]([CH:10]=[O:11])[CH2:9][C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@@H]2O[C@H](CO)C[C@@H]2O1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2O[C@H](C=O)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
To a stirred solution of [(3aS,5S,6aS)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanol (compound 25e, 2 g, 11.5 mmol) in THF (20 mL) was added Dess-Martine periodinane (7.2 g, 17.2 mmol). After being stirred room temperature for 2 hours, the resulting solution was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:3 EtOAc in petroleum ether) to afford 1.2 g of (3aS,5S,6aS)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde (compound 25f). MS obsd. (ESI+) [(M+NH4)+]: 190.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH2:15](OCC)[CH3:16]>>[CH2:15]([CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[NH:6]1)[CH3:16]
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: CCOCC
Product: CCC1Nc2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
A stirred solution of phenanthridine (25 g, 139 mmol) in anhydrous diethyl ether (100 mL) was cooled to −78° C., and treated drop-wise under nitrogen via syringe with a solution of 0.62 M ethyllithium1 in diethyl ether (225 mL, 139 mmol). The yellow solution was warmed to room temperature and stirred for three to four hours. The reaction was cooled to −78° C., and quenched with water. After warming to room temperature, the reaction mixture was extracted with diethyl ether, and the organic phase was washed sequentially with water and a saturated, aqueous, sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated in vacuo, to yield 6-ethyl-5,6-dihydrophenanthridine as a crude solid (26 g, 124 mmol, 89%).
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C@@H:4]([C:6]([O:8]C)=[O:7])[CH2:3][C@H:2]1[C:10]([O:12][CH3:13])=[O:11].[OH-].[Na+].Cl>C1COCC1>[C:17]([O:16][C:14]([N:1]1[C@H:2]([C:10]([O:12][CH3:13])=[O:11])[CH2:3][C@H:4]([C:6]([OH:8])=[O:7])[CH2:5]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Yield: 70.1 %

Procedure:
To a solution of (2S,4S)-1-tert-butyl 2,4-dimethyl pyrrolidine-1,2,4-tricarboxylate (9.56 g, 33.3 mmol) in THF (70 mL) at 0° C. (external temperature, ice bath) was added NaOH (1N aqueous, 33 mL, 33.3 mmol) dropwise over 15 min. The solution was stirred at 0° C. for 5h before acidification with HCl (1N). The solution was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by silica gel chromatography (2% to 5% to 10% MeOH/CH2Cl2) to provide (3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidine-3-carboxylic acid (6.38g, 70%).
Reaction SMILES: [NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:5]2[C:6]([C:9](O)=[O:10])=[CH:7][O:8][C:4]=2[CH:3]=1.C[CH2:16][N:17]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.CN.Cl>CN(C=O)C>[NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:5]2[C:6]([C:9]([NH:17][CH3:16])=[O:10])=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: Nc1cc2occ(C(=O)O)c2cc1Br
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1coc2cc(N)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 6-amino-5-bromobenzofuran-3-carboxylic acid (51 g, 199 mmol) in dry DMF (500 mL) was added EDCI (53.1 g, 298.77 mmol) and HOBT (40.4 g, 299 mmol). The reaction mixture was stirred at room temperature for 2 h, and then Et3N (60.5 g, 598 mmol) and MeNH2.HCl (40.3 g, 598 mmol) were added to the reaction mixture. After stirring for another 2 hours, the reaction mixture was concentrated in vacuum and then 300 mL Na2CO3 (sat., a.q.) was added to the mixture. The resulting solid was filtered to give the crude product, which was purified by column chromatography (DCM:MeOH=30:1) to give the product 6-amino-5-bromo-N-methylbenzofuran-3-carboxamide (38 g, yield: 71%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.19˜8.21 (m, 2H), 7.98 (s, 1H), 6.97 (s, 1H), 5.46 (br s, 2H), 2.75 (d, J=4.4 Hz, 3H). MS (M+H)+: 269/271.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[Cl:20][C:21]1[CH:30]=[CH:29][C:24]([CH:25]=[CH:26][CH2:27]Cl)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:30]=[CH:29][C:24]([CH:25]=[CH:26][CH2:27][N:7]2[C:6](=[O:19])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=3)=[N:8]2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(-c2ccc(SC)cc2)n[nH]c1=O
Reactant: ClCC=Cc1ccc(Cl)cc1
Product: COC(=O)c1cc(-c2ccc(SC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 82.3 %

Procedure:
Using 4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 4-chlorocinnamyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 82.3%.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[C:15](=[O:16])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:21][Li]>O1CCCC1.C(OCC)C>[OH:16][C:15]1([CH3:21])[C:8]2[CH:7]=[CH:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:10]=3[C:9]=2[CH:11]=[CH:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: [Li]C
Reactant: O=c1c2ccccc2ccc2c1ccc1ccccc12
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)c2ccccc2C=Cc2c1ccc1ccccc21

Procedure:
To a solution of 7H-benzo[4,5]cyclohepta[1,2-a]naphthalen-7-one (1.75 g, prepared by the method of Bergmann et al, J. Org. Chem., 1963, 28, 3341) in dry tetrahydrofuran (40 ml) at 0° C. under nitrogen was added a solution of methyl lithium in diethyl ether (8 ml of 1.4M). After 90 minutes at 0° C. the reaction was quenched by the dropwise addition of water (20 ml) and the reaction mixture extracted into diethyl ether (2×75ml). dried (Na2SO4), filtered and the solvents removed under reduced pressure to give a light brown oil (1.9 g).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[N+:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Cl)([O-:26])=[O:25].[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=2)[C:14]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:13]=2[O:12]1
Reactant: COc1ccc2c(c1)OC(CCO[Si](C)(C)C(C)(C)C)C(=O)N2
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [Br-]
Agent: [K+]
Product: COc1ccc2c(c1)OC(CCO)C(=O)N2Cc1cccc([N+](=O)[O-])c1
Yield: 30 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-7-methoxy-3-oxo-2H-1,4-benzoxazine by methods F and I, alkylating with 3-nitrobenzyl chloride, in 30% yield, mp 116°-118° C.; MS (CI) MH+ 359; IR (KBr) 3306, 3086, 2926, 2872, 1628, 1595, 1476, 1309, 1290, 1255, 1087, 999, 713, 458 cm-1 ; 1H NMR (DMSO-d6) δ8.14 (s, 1H), 8.11 (s, 1H), 7.63 (m, 2H), 6.97 (d, 1H, J=8.93 Hz), 6.66 (d, 1H, J=2.42 Hz), 6.53 (d, 1H, J=8.87 Hz), 5.26 (s, 2H), 4.87 (dd, 1H, J=8.98, 3.76 Hz), 4.72 (t, 1H, J=5.23 Hz), 3.68 (s, 3H), 3.61 (m, 2H), 2.01 (m, 1H), 1.90 (m, 1H). Anal. Calc'd for C18H18N2O6 : C 60.33 H 5.06, N 7.82. Found: C 59.96, H 5.08, N 7.62.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:24])=[C:4]([CH3:23])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:6]=2[C:21]=1[CH3:22].[C:25](O)(=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29].S(=O)(=O)(O)O>C(OCCCC)CCC>[CH:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:7]2[C:6]3[C:21]([CH3:22])=[C:2]([O:1][C:25]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])[C:3]([CH3:24])=[C:4]([CH3:23])[C:5]=3[O:9][C:8]2([CH3:10])[CH3:11])=[CH:13][CH:14]=1)([CH3:20])[CH3:19]
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: O=C(O)CCC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCCCOCCCC
Product: Cc1c(C)c2c(c(C)c1OC(=O)CCC(=O)O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reaction time: 1 h
Yield: 23.7 %

Procedure:
To a solution of 2.0 g (6.16 m mol) of 5-hydroxy-2,2,4,6,7 -pentamethyl-3-(4-isopropylphenyl)-2,3-dihydrobenzofuran obtained in Example 20 in 10 ml of dibutyl ether were added 740 mg (7.4 m mol) of anhydrous succinic acid and 0.1 ml of conc. sulfuric acid. This was stired at 80° C. for 1 hour. After cooling, the reaction mixture was washed with water, dried and concentrated. The resulting residue was purified by silica gel chromatography (eluted by isopropyl ether). Addition of isopropyl ether-hexane to the resulting concentrate gave 620 mg (yield 23.7%) of 3[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yloxycarbonyl]propionic acid. mp. 141°-142° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([O:21]CC4C=CC=CC=4)[CH:18]=[CH:17][C:15]=3[CH:16]=2)[O:8][C:7](=[O:29])[C:6]=1[CH3:30])(=[O:3])[CH3:2]>CCO.O1CCOCC1.[Pd]>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=3[CH:16]=2)[O:8][C:7](=[O:29])[C:6]=1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(-c2cc3ccc(OCc4ccccc4)cc3o2)oc(=O)c1C
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(=O)Oc1c(C)c(-c2cc3ccc(O)cc3o2)oc(=O)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-acetyloxy-6-(6-(benzyloxy)benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one (500 mg) in EtOH (50 ml) and 1,4-dioxane (50 ml) there was added 10% Pd/C (100 mg), and the mixture was vigorously stirred at room temperature for 3 hours under a hydrogen gas atmosphere. The reaction solution was celite filtered, and then the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1) to obtain 4-acetyloxy-3,5-dimethyl-6-(6-hydroxybenzofuran-2-yl)-2H-pyran-2-one.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[CH3:31]>>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[CH3:31])=[CH:9][C:8]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:7]1)[CH3:20]
Reactant: CCOC(Cn1nc(-c2cnccn2)cc1N)OCC
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Product: CCOC(Cn1nc(-c2cnccn2)cc1Nc1cc([N+](=O)[O-])ccc1C)OCC

Procedure:
Analogously to Example 13A/Step 1, 1.16 g (4.18 mmol) of the compound of Example 59A and 994 mg (4.60 mmol) of 2-Bromo-4-nitrotoluene gave 1.64 g (86% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NCc1cccnc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cccnc1Cl
Yield: 47.5 %

Procedure:
To a solution of (2-chloro-3-pyridyl)methanamine (300 mg, 2.10 mmol) in dichloromethane (2 mL) at room temperature is added acetic acid anhydride (198.88 mL, 2.10 mmol) and triethylamine (293.26 mL, 2.10 mmol). After 1 h the reaction is quenched with saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate and the solvent evaporated in vacuo to afford 184 mg of N-[(2-chloro-3-pyridyl)methyl]acetamide. MS (m/z): 185 (M+1)
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=O)[C:12]([N+:17]([O-:19])=[O:18])=[CH:13][NH:14]3)=[CH:9][C:8]=2[O:21][CH3:22])=[C:5]([CH3:23])[O:4][N:3]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:23])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(=O)c([N+](=O)[O-])c[nH]c2cc1-c1c(C)noc1C
Product: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 63.4 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitroquinolin-4(1H)-one (for a preparation see Intermediate 6) (4.78 g, 15.16 mmol) was dissolved in POCl3 (10 ml, 107 mmol) and the mixture was heated at 110° C. for 3 h, then cooled and evaporated in vacuo, The residue was suspended in toluene (20 ml) and evaporated in vacuo, then the residue was suspended in DCM (100 ml) and saturated sodium hydrogen carbonate solution (100 ml) and stirred for 10 min. The organic layer was dried and evaporated and the residue dissolved in DCM (10 ml) and loaded onto a 100 g silica column, then eluted with 0-60% EtOAc/cyclohexane to give 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole (3.21 g, 9.62 mmol, 63.4% yield) as a bright yellow powder. LCMS (formate) Rt 1.13 min, MH+ 334
Reaction SMILES: [ClH:1].Br[C:3]1[CH:13]=[C:12]([O:14]C(=O)C)[C:11]([O:18][CH3:19])=[CH:10][C:4]=1[CH2:5][NH:6][C:7](=[O:9])[CH3:8].[OH-].[Na+]>O1CCOCC1>[Cl:1][C:3]1[CH:13]=[C:12]([OH:14])[C:11]([O:18][CH3:19])=[CH:10][C:4]=1[CH2:5][NH:6][C:7](=[O:9])[CH3:8]
Reactant: Cl
Reactant: COc1cc(CNC(C)=O)c(Br)cc1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(CNC(C)=O)c(Cl)cc1O

Procedure:
10% Aq. hydrochloric acid (2.5 ml) was added to a solution of 2-chloro-4-acetoxy-5-methoxy-N-acetyl-benzylamine 2 (0.45 g, 1.66 mmol) in dioxane (15 ml) and the mixture was refluxed for 2 hours. After cooling, the solvent was reduced under vacuum and the residue was basified with 10% aq. NaOH. The resulting solid was collected by filtration, washed with cold water and dried to furnish the title compound as white solid in quantitative yield.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]N2C3C=CC=CC=3N=N2)=[CH:10][CH:9]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=NC2C=CC=CC=2)=[CH:27][CH:26]=1>CN(C=O)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=2)=[CH:27][CH:26]=1
Reactant: Fc1ccc(C=Nc2ccccc2)cc1
Reactant: Fc1ccc(Cn2nnc3ccccc32)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(C#Cc2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
To potassium t-butoxide (1.5 g, 13.4 mmol) in DMF (15 mL) at 75° C. was added as quickly as possible and all at once [(4-fluorophenyl)methyl]-1H-benzotriazole (1.14 g, 5 mmol) and (4-fluorophenyl)methylenebenzenamine (1.00 g, 5 mmol) dissolved in DMF (10 mL). Within a minute the solution is poured into ice-cold water (75 mL) crystallizing the title compound which was filtered and then chromatographed (PE). The acetylene 0.54 g (50%) recrystallizes as needles: mp 95°-96° C. (MeOH); (lit.1 94°-95° C.).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:7]2)[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:4][N:3]1[CH2:29][C:30]1[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=1)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].[BH4-].[Na+]>C(O)C>[OH:22][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:14][CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][C:6]2([N:5]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:4][N:3]([CH2:29][C:30]3[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=3)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:2]2=[O:1])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(O)c4ccccc4)CC3)C2=O)c1
Temperature: 41 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A mixture of tert-butyl 3-((4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (1.45 g, 2.56 mmol, 1 equiv) in ethanol was warmed to 41° C. Sodium borohydride (194 mg, 5.13 mmol, 2 equiv) was slowly added and the reaction stirred as such for 30 minutes. It was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and the mixture was partitioned between ethyl acetate and water, followed by a brine wash. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.45, gradient—1%-10% methanol in dichloromethane) to afford the title compound as a cream solid (1.2 g, 83%); 1H NMR (400 MHz, DMSO-d6): δ 1.52 (s, 9H); 1.59-1.66 (m. 5H); 2.33-2.34 (m, 2H); 2.51-2.52 (m, 2H); 2.68-2.73 (m, 4H); 4.57-4.61 (m, 5H); 5.51 (d, 1H, J=3.6 Hz); 6.74-6.77 (m, 1H); 6.82 (s, 2H); 6.85 (s, 1H); 7.18-7.23 (m, 3H); 7.29-7.36 (m, 4H); 7.5-7.53 (m, 2H); 7.79 (bs, 1H); 7.82-7.84 (m, 1H); MS for C35H43N3O4 m/z 570.33 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:2]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:1]
Reactant: COC(=O)Cc1ccccc1Oc1cccc(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.4 %

Procedure:
Methyl 2-(3-hydroxymethylphenoxy)phenylacetate (10.0 g, preparared as described in Example 17) and celite (10 g) were mixed in methylene chloride (100 ml), and pyridinium chlorochromate (15.85 g) was added in one portion. After stirring at room temperature for 2.5 hours, the mixture was filtered and the filtrate was evaporated to give methyl 2-(3-formylphenoxy)phenylacetate as an orange oil (8.48 g), which was pure enough to use without further purification.
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:28]1([Mg]Br)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[OH:15][C:14]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:2]2[N:1]=[CH:6][C:5](=[O:7])[NH:4][C:3]=2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1cnc2c([nH]1)-c1ccccc1C2(O)c1ccccc1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione (2 g) was dissolved in dry THF (50 ml). Triethylamine (1.6 ml) was added and trimethylsilyl chloride (1.4 ml) dissolved in THF (10 ml) was added dropwise at room temperature. The mixture was stirred overnight and the precipitate filtered off. Phenylmagnesium bromide (20 mmol) in THF (10 ml) was subsequently added dropwise under nitrogen, and the resulting mixture stirred at room temperature for 3 days. Subsequent evaporation followed by addition of water and addition of HCl (1N) to slightly acidic solution resulted in precipitation of yellow crystals (2.7 g). The precipitate was purified on silica gel column using methylene chloride/methanol (9/1) as eluent resulting in 1.2 g pure title compound. M.p.>270° C. The MS showed the molecular ion 276. 1H-NMR (DMSO-d6, δ): 6.39 (s, 1H), 7.15-7.5 (m, 8H), 7.82 (s+m, 2H), 12.6 (s, 1H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:10]=3[N:11]=[CH:12][C:13]=2[N+:14]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl>CCO>[CH2:4]1[CH2:5][CH2:6][CH:1]([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][N:11]=[C:10]3[N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:21])=[O:22])[CH:18]=[CH:19][C:9]=23)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCC4)c([N+](=O)[O-])cnc32)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCC4)c(N)cnc32)cc1
Temperature: 75 °C
Yield: 78.6 %

Procedure:
To a mixture of N-cyclohexyl-5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine (0.111 g, 0.268 mmol, prepared using K.1 from Example #21 Step D with 4-methylbenzene-1-sulfonyl chloride, L with cyclohexylamine) in EtOH (2.5 mL) was added tin (II) chloride dihydrate (0.060 g, 0.268 mmol). The reaction mixture was heated at about 75° C. for about 75 min. Tin (II) chloride dihydrate (0.030 g, 0.134 mmol) was added and the reaction mixture was heated at about 75° C. for about 5 h. Additional tin (II) chloride dihydrate (0.060 g, 0.268 mmol) was added and the reaction mixture was heated at about 75° C. for about 14 h. The solvent was removed under reduced pressure. The residue was diluted with EtOAc (25 mL) and washed with saturated aqueous NaHCO3 (25 mL) and brine (25 mL). The organic portion was separated. The aqueous portion was extracted with EtOAc (3×25 mL). The organic extracts were combined, dried over MgSO4, filtered, and concd under reduced pressure to give N-4-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.081 g, 79%) as a brown oil: LC/MS (Table 1, Method n) Rt=0.82 min; MS m/z 385 (M+H)+.