Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:6]=2[C:5]=1[S:14]([O-:17])(=O)=[O:15])(O)=[O:2].[Na+].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-:25].[Cl-:26].[Cl-].[P+3]=O>>[Cl:13][C:10]1[CH:11]=[CH:12][C:6]2[C:5]([S:14]([Cl:25])(=[O:17])=[O:15])=[C:4]([C:1]([Cl:26])=[O:2])[S:8][C:7]=2[CH:9]=1
Reactant: O=C(O)c1sc2cc(Cl)ccc2c1S(=O)(=O)[O-]
Reactant: [Cl-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=[P+3]
Agent: [Na+]
Product: O=C(Cl)c1sc2cc(Cl)ccc2c1S(=O)(=O)Cl
Yield: 72 %

Procedure:
Prepared analogous to Example 1(b) from monosodium 2-carboxy-6-chloro-benzo-[b]-thiophene-3-sulfonate and phosphorus (V)-chloride in the presence of phosphorus oxide trichloride with a yield of 72% of theory. The product, which crystallized upon cooling, was used in the next step without further purification.
Reaction SMILES: [OH:1][C@@:2]1([CH2:23][CH2:24][CH3:25])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=[O:22])[CH2:14][C@@H:15]1[CH3:21])[CH2:10][CH2:9]3.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:26]([O:1][C@@:2]1([CH2:23][CH2:24][CH3:25])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=[O:22])[CH2:14][C@@H:15]1[CH3:21])[CH2:10][CH2:9]3)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCC[C@]1(O)CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCC[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
1.5 g of 17β-hydroxy-1α-methyl-17α-n-propyl-5α-androstan-3-one is allowed to stand at room temperature in 6 ml of pyridine with 3 ml of acetic anhydride for 16 hours, after the addition of 75 mg of 4-dimethylaminopyridine. After the mixture has been precipitated into ice water and recrystallized from hexane, 1.3 g of 17β-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3-one is obtained, m.p. 128°-129° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CC(C)=O.O>[N:5]1[CH:6]=[CH:7][C:2]([C:1]([N:23]=[N+:24]=[N-:25])=[O:9])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccncc1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccncc1
Temperature: -10 °C

Procedure:
6.15 g of isonicotinic acid and 5.55 g of triethylamine were dissolved in 50 ml of acetone. 6 g of ethyl chloroformate were added dropwise to this solution which had been cooled to -10° C. After 2 hours a solution of 5 g of NaN3 dissolved in 20 ml of H2O was added dropwise at 0° C. After 1 hour at room temperature the solid was filtered off and discarded. The solution was distilled at room temperature and the residue was extracted with dichloromethane. After drying over MgSO4 the solvent was distilled off and the liquid remaining behind was filtered over silica gel with dichloromethane as the eluent. There was obtained 4-pyridylcarboxylic acid azide as a colorless liquid which crystallized in a deep freezer (-18° C.). IR: 2141, 2190 cm-1 (N3).
Reaction SMILES: [CH3:1][C:2]1([C:15](OCC)=[O:16])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Li+].[BH4-].Cl>C1COCC1>[OH:16][CH2:15][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CO)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a cold (−20° C.) solution of 1-tert-butyl 3-ethyl 3-methyl-1,3-piperidinedicarboxylate (2.3 g, 8.48 mmol) in dry THF was added LiBH4 (2M in THF, 10.6 mmol), and the stirring was continued overnight. The reaction mixture was allowed to warm to room temperature. The reaction mixture was cooled by ice water and acidified (pH 5-6) with aqueous 1N HCl. The mixture was concentrated under reduced pressure, then extracted with ethyl acetate. The organic phase was separated, dried over MgSO4, filtered, and evaporated. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate, 4:1-3:1) to give tert-butyl 3-(hydroxymethyl)-3-methyl-1-piperidinecarboxylate as a colorless oil form (1.5 g, yield; 78%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1.Cl.[CH3:33][NH:34][CH3:35].Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[OH:1][CH2:2][C:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26]([N:34]([CH3:35])[CH3:33])=[O:27])=[CH:24][N:23]=5)=[CH:20][CH:21]=4)[CH2:14][CH2:15]3)=[N:11][N:12]=[C:5]2[CH2:4]1
Reactant: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)O)cn5)cc4)CC3)n2CCS1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)nc1
Yield: 95.9 %

Procedure:
A solution of the compound (150 mg, 0.344 mmol) obtained in Example 66, dimethylamine hydrochloride (140 mg, 1.72 mmol), N,N-dimethylaminopyridine (4 mg, 34 μmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) in N,N-dimethylformamide (3.00 mL) was stirred at room temperature for 1.5 h. Saturated aqueous sodium hydrogencarbonate (100 mL) was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with water and dried with anhydrous sodium sulfate. Then the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (153 mg, 96%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1([CH3:31])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NC(=O)c1ccccn1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1NC(=O)c1ccccn1
Yield: 74.7 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(2-(picolinamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (44 mg, 0.1 mmol, 1.0 eq.) and 1.3 mL aqueous solution of sodium hydroxide (2 M, 2.6 mmol, 25 eq.) in tetrahydrofuran (3 mL) was stirred at reflux for 3 h. Thin layer chromatography indicated that the starting material was consumed completely. The tetrahydrofuran was removed under reduced pressure and the residue was acidified to pH 5-6 with 1 M hydrochloric acid. Then a lot of white precipitates were formed and collected by filtration to afford 30 mg of 3,3-dimethyl-2-(2-(picolinamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid; yield: 65%. MS (ESI+APCI) M+1=402.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[C:27]([CH3:28])=[CH:26][C:25](Br)=[CH:24][N:23]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:30][N:31](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[C:27]([CH3:28])=[CH:26][C:25]([C:30]#[N:31])=[CH:24][N:23]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)cnc1-c1ccc2c(c1)CC(C1CCN(C(=O)OC(C)C)CC1)O2
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)cnc1-c1ccc2c(c1)CC(C1CCN(C(=O)OC(C)C)CC1)O2
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[5-(5-bromo-3-methyl-pyridin-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester (26 mg), zinc cyanide (7.3 mg), and 1,1′-bis(diphenylphosphino)-ferrocene (3.2 mg) in N,N-dimethylformamide (0.5 mL) is sparged with argon for 5 min. Tris(dibenzylideneacetone)dipalladium (2.6 mg) is added and the resulting mixture is stirred at 120° C. for 3 h. After cooling to room temperature, dichloromethane is added and the mixture is extracted with aqueous K2CO3 solution (10%). The organic phase is washed with brine, dried (MgSO4), and the solvent is evaporated. The residue is chromatographed on silica gel (dichloromethane/methanol 95:5) to give the title compound. Yield: 12 mg (52% of theory); LC (method 2): tR=1.49 min; Mass spectrum (ESI+): m/z=406 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:28])[C:25]#[C:26][CH3:27])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:28])/[CH:25]=[CH:26]\[CH3:27])=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: C/C=C\C(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
Lindlar's catalyst (0.005 g, 0.001 mmol) was added in one portion to a stirred solution of 4-[4-(1-oxo-but-2-ynylamino)-benzenesulfonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.05 g, 0.11 mmol) in methanol (5 ml) at room temperature, the resulting mixture was then stirred at room temperature under a hydrogen atmosphere for 2 hours. After this time, the reaction mixture was filtered through celite and concentrated under vacuum to give the title compound (0.02 g, 40% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([F:13])=[C:8]([F:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].C([Li])(CC)C.[O:19]1[C:23]2([CH2:28][CH2:27][CH:26]([CH:29]3[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]3)[CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[O:19]1[C:23]2([CH2:24][CH2:25][CH:26]([CH:29]3[CH2:34][CH2:33][C:32]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:7]([F:13])[C:8]=4[F:12])([OH:35])[CH2:31][CH2:30]3)[CH2:27][CH2:28]2)[O:22][CH2:21][CH2:20]1
Reactant: CCCCOc1cccc(F)c1F
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(C2(O)CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Reaction time: 2 h
Yield: 99.6 %

Procedure:
3-Butoxy-1,2-difluorobenzene (7) (10.0 g) and THF (200 ml) were added to a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00 M, in n-hexane and cyclohexane solution; 64.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Successively, 4-(1,4-dioxaspiro[4.5]decan-8-yl)-cyclohexanone (21) (12.8 g) in THF (50 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., while the mixture was allowed to come to 25° C. The reaction mixture was poured into a 3%-aqueous solution of ammonium chloride (100 ml) and ethyl acetate (100 ml) in a vessel and mixed with them. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to leave 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-butoxy-2,3-difluorophenyl)-cyclohexanol (22) (22.7 g). The resulting compound (22) was a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][CH2:8][CH:5]2[CH2:4][CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][CH2:6]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC1(C)CCC(CCO)CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CCC(CCOS(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.3 %

Procedure:
To a solution of 2-(4,4-dimethylcyclohexyl)-1-ethanol (Preparation 15, 1.45 g, 9 mmol) and 4-bromobenzenesulfonyl chloride (2.53 g, 10 mmol) in dichloromethane (30 ml) was added triethylamine (1.9 ml, 13.5 mmol), and the reaction mixture was allowed to stir at room temperature for 24 h. After a further addition of 4-bromobenzenesulfonyl chloride (2.53 g, 10 mmol) and triethylamine (1.9 ml, 13.5 mmol), the reaction mixture was heated under reflux for 1 h. After allowing the reaction mixture to cool to room temperature, the mixture was treated with 2N aqueous hydrochloric acid (100 ml) and the phases were separated. The organic extract was dried (MgSO4), filtered and concentrated in vacuo to afford the crude product. The residue was purified by silica (80 g) column chromatography eluting with diethyl ether:hexane (1:20) to give the title compound as a colourless oil (450 mg, 13%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:26])[C:23]([NH2:25])=[O:24])[CH:17]=1)[C:10]([CH3:28])([CH3:27])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:27][C:10]1([CH3:28])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:26])[C:23]([NH2:25])=[O:24])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N(C)C(N)=O)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C(N)=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 60 °C
Reaction time: 36 h
Yield: 15.8 %

Procedure:
A mixture of 3,3-dimethyl-2-[3-(1-methyl-ureido)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (190 mg, 0.5 mmol) in methanol (5 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 36 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-[3-(1-methyl-ureido)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (28 mg, 15%) as a white solid: LC/MS m/e calcd for C20H23N3O3 (M+H)+: 354.42, observed: 354.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:13].C(=O)([O-])[O-].[K+].[K+].F[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29].O>CN(C=O)C>[Cl:27][C:25]1[CH:26]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([S:13][C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:7][C:2]=2[Cl:1])[CH:24]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CCS(=O)(=O)c1ccc(S)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2[N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from step (i) (1.60 g), potassium carbonate (0.934 g) and 2-fluoro-4-chloro-nitrobenzene (1.18 g) in DMF (20 ml) was stirred at RT overnight. Water (200 ml) was added and the mixture extracted with ethyl acetate. The organics were dried, evaporated under reduced and the residue purified by chromatography on silica eluting with isohexane/diethylether 4:1, yield 0.80 g.
Reaction SMILES: F[C:2]1[C:7]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:6]=2[CH:5]=[C:4]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:3]=1)=[CH:13][C:12]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=3.[CH3:33][O-:34].[Na+]>CO>[CH3:33][O:34][C:2]1[C:7]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:6]=2[CH:5]=[C:4]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:3]=1)=[CH:13][C:12]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=3
Reactant: C[O-]
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1c2cc(-c2cccnc2)nc1F
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2cccnc2)cc2c1Oc1ccc(-c3cccnc3)cc1[C@@]21COC(N)=N1
Temperature: 25 °C

Procedure:
A solution of (S)-1-fluoro-3,7-di(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (40 mg, 0.094 mmol) and sodium methoxide (52.4 μL, 0.940 mmol) in 15 mL of MeOH was heated to 65° for 5 h. After cooling to rt, the reaction was evaporated to dryness and was partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated and the organics were dried over sodium sulfate, filtered and evaporated to dryness. Flash column (CH2Cl2 to CH2Cl2/MeOH=100:5 to 100:10 to 100:20) gave (S)-1-methoxy-3,7-di(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine as an off white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13](N(CC)CC)C.CI.[ClH:22]>CC(C)=O.CCOCC.CO>[ClH:22].[ClH:22].[CH3:13][N:11]1[CH2:10][CH2:9][NH:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12]1
Reactant: CCN(CC)CC
Reactant: c1ccc(C2CNCCN2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CI
Product: CN1CCNC(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To an ice-cooled stirred solution of 5.45 g (0.033 mol) of 2-phenylpiperazine and 5.3 g (0.53 mol) of triethylamine in 580 ml of acetone was added dropwise over 20 minutes a solution of 4.8 g (0.033 mol) of methyl iodide in 20. ml of acetone. The resulting mixture was stirred at 0° C. for 1 h and then allowed to gradually warm to ambient temperature over 3 hours. The residue obtained upon concentration of the reaction mixture was dissolved in 200 ml of ether and treated with a solution of methanol and ether saturated with gaseous hydrochloric acid to give 4.5 g (54%) of 1-methyl-3-phenylpiperazine dihydrochloride as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][C:10]([CH3:12])=O.CC(O)=O.[BH3-]C#N.[Na+]>CO>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][CH:10]([CH3:12])[CH3:9])[CH:3]=[N:4][CH:5]=1
Reactant: Nc1cncc(Br)c1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Nc1cncc(Br)c1
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromopyridin-3-amine (XXII) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 μL, 4.02 mL). The pH was adjusted to 4 using HOAc and stirred for 30 min. NaCNBH3 (272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% hexane→90:10 hexane:EtOAc) to produce 5-bromo-N-isopropylpyridin-3-amine (XLIV) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.12 (d, J=6.3 Hz, 6H), 3.55-3.59 (m, 1H), 6.03 (d, J=7.9 Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J=2 Hz, 1H), 7.90 (d, J=2 Hz, 1H); ESIMS found C8H11BrN2 m/z 215 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14]C1CCCCO1)=[O:12].Cl>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][OH:14])=[O:12]
Reactant: CC(CCc1ccc(-c2ccccc2)cc1F)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(CCc1ccc(-c2ccccc2)cc1F)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 17.5 %

Procedure:
4-(3-Fluorobiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (170 mg, 0.382 mmol) was dissolved in 5 mL of dichloromethane at ambient temperature. To this solution was added 4M HCl (2.86 mL, 11.5 mmol) in dioxane and the solution was stirred at ambient temperature for 5 minutes. The reaction was quenched by the addition of 0.5 mL of methanol. After stirring for an additional 5 minutes, the reaction was concentrated in vacuo. Purification was performed using Shimadzu prep HPLC to provide the title compound (24.4 mg, 14.5%) LC-MS m/z 366.5 (M+1) 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.68 (s, 3H) 2.06-2.16 (m, 1H) 2.53-2.59 (m, 1H) 2.60-2.67 (m, 1H) 2.79-2.89 (m, 1H) 3.06 (s, 3H) 7.30-7.33 (m, 1H) 7.31-7.33 (m, 1H) 7.34-7.37 (m, 1H) 7.38 (d, J=3.12 Hz, 1H) 7.40-7.42 (m, 1H) 7.43-7.46 (m, 2H) 7.58-7.64 (m, 2H)
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:32])=[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)[C:10]([CH:17]([CH3:19])[CH3:18])=[N:11]2>O1CCCC1.[OH-].[Li+]>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH:17]([CH3:18])[CH3:19])[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)=[C:8]2[CH3:32]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(Cl)ccc(OCC(=O)O)c12
Yield: 71.1 %

Procedure:
A solution of [8-chloro-2-isopropyl-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.087 g) in tetrahydrofuran (3.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.5 mL) was stirred at room temperature for three hours. The mixture was concentrated under reduced pressure and the pH adjusted to 4 by the addition of 0.1 M aqueous hydrochloric acid (3 mL). The mixture was extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane, ethyl acetate and formic acid (1:0:0:0.001 to 0:1:0.001 by volume) to afford title compound as pale yellow solid (0.06 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34]([C:36](O)=[O:37])[N:33]=[N:32]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:34]4[N:33]=[N:32][N:31]([CH3:30])[CH:35]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cn1cc(C(=O)O)nn1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cn(C)nn2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1-methyl-1H-1,2,3-triazole-4-carboxylic acid (19 mg, 0.15 mmol).