Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N:11]([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH3:21]N(C)C=O.[S:26]([O:31]C)([O:29][CH3:30])(=[O:28])=[O:27]>C(OCC)(=O)C>[CH3:30][O:29][S:26]([O-:31])(=[O:28])=[O:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@H](C)N(C)[C@@H](C)c2ccccc2)c1
Reactant: COS(=O)(=O)OC
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: COS(=O)(=O)[O-]
Product: COc1cccc([C@H](C)[N+](C)(C)[C@@H](C)c2ccccc2)c1
Temperature: 60 °C
Yield: 72 %

Procedure:
Mix 5.5 g (0.02 mol) of (S)-1-(3-methoxyphenyl)-N-methyl-N—((S)-1-phenylethyl)ethanamine (formula IV) with 12 ml N,N-dimethylformamide and 12.6 g (0.1 mol) of dimethyl sulfate at room temperature, heat the mixture to 60° C. for 24 hours. Let it cool to room temperature, and add 100 ml of ethyl acetate. A light yellow solid is produced. Filter and dry it to receive 5.7 g light yellow solid with a yield of 72%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH:18]([CH3:20])[CH3:19])[NH:5][C:6]([O:8]C1C=CC([N+]([O-])=O)=CC=1)=O.[CH:22]([C:25]1[O:26][CH:27]=[C:28]([CH2:30][NH:31][CH3:32])[N:29]=1)([CH3:24])[CH3:23]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH:18]([CH3:19])[CH3:20])[NH:5][C:6]([N:31]([CH3:32])[CH2:30][C:28]1[N:29]=[C:25]([CH:22]([CH3:23])[CH3:24])[O:26][CH:27]=1)=[O:8]
Reactant: CNCc1coc(C(C)C)n1
Reactant: COC(=O)[C@@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)N(C)Cc1coc(C(C)C)n1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
A solution of N-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester (0.903 g, 0.00305 mol) in anhydrous DMF (6 mL) was added to a solution of 2-isopropyl-4-(((N-methyl)amino)methyl)oxazole (9, 0.470 g, 0.00305 mol) in anhydrous DMF (6 mL) under argon, and the yellow solution was stirred at room temperature for 30 min. Solvent was removed by rotary evaporation in vacuo and the resulting oil dried on high vacuum for 1 hr. The residue was applied to a 150 g SiO2 flash column and eluted with 20% EtOAc/CH2Cl2 and 3% MeOH/CH2Cl2. The material obtained after concentration of the product fractions was repurified on a 100 g SiO2 flash column with a gradient of MeOH/CH2Cl2 (1%, 2%, 3%) to obtain the desired compound as an oil (0.515 g, 0.00165 mol, 54 %): 1H NMR (CDCl3) δ 0.97 (dd, J1 =9 Hz, J2 =6.9 Hz, 6H), 1.33 (d, J=6.9 Hz, 6H), 2.11-2.23 (m, 1H), 2.98 (s, 3H), 3.00-3.13 (m, 1H), 3.77 (s, 3H), 4.23-4.36 (m, 2H), 4.36-4.42 (m, 1H), 5.79-5.86 (br d, 1H), 7.46 (s, 1H). Mass spectrum: (M+H)+ =312.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[N:9][N:10]=[C:4]2[CH:3]=1.[Br:11]N1C(=O)CCC1=O.C1C=CC=CC=1.BrN1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[N:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccn2nnnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: BrCc1ccn2nnnc2c1
Yield: 98.8 %

Procedure:
7-Methyl tetrazolo [1,5-a]pyridine [Boyer, et al., J. Am. Chem. Soc., 82, 2218 (1960)] (23 g, 173 mmole), benzene N-bromosuccinimide (30.6 g. 173 mmole) and benzoyl peroxide (100 mg) in 1.5 liters of benzene is refluxed overnight. More N-bromosuccinimide (15.3 g, 86.5 mole) is added and the reflux is maintained for several hours. The mixture is cooled and washed with 100 ml 20% sodium hydroxide and then with water. It is dried over calcium chloride, evaporated to dryness to yield 36.4 g of a mixture of 7-bromomethyltetrazolo [1,5-a]pyridine (63%) 7-dibromomethyltetrazolo [1,5-a]pyridine (24%) and 7-methyltetrazolo [1,5-a]pyridine (13%). Two triturations of this mixture with 500 ml of ether-hexane 1:1 (v/v) affords 25 g of a mixture consisting of 82% monobromo derivative, 13% dibromo derivative and 5% of starting material. This mixture is used for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:20][CH2:19]2)[C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:7])=[CH:33][CH:34]=1)(=[O:37])[CH3:36]
Reactant: Cc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc(C)cc2)cc1
Yield: 95.4 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(4-methylphenyl)benzamide (452.7 mg, 0.99 mmol) and acetic anhydride (0.122 ml, 1.19 mmol), the procedure of Inventive Example 94 was repeated to obtain 473.6 mg (95.4%) of the title compound in a light brown amorphous form.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:25][CH:26]=2)[CH:15]=1)(=O)=O>>[N:1]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:25][CH:26]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCCc1cccc(OCc2coc(/C=C/c3ccccc3)n2)c1
Product: C(=C/c1nc(COc2cccc(CCCn3ccnc3)c2)co1)\c1ccccc1
Yield: 63 %

Procedure:
In substantially the same manner as in Working Example 8, imidazole was allowed to react with 3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate to give 4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 63%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 86-87° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:25][C:8]2[C:9]3[CH:10]=[CH:11][C:12]([C:16](=[O:24])[NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:13][C:14]=3[S:15][C:7]=2[C:6]=1[O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:4].O>C1COCC1>[C:28]([CH2:27][O:26][C:6]1[C:7]2[S:15][C:14]3[CH:13]=[C:12]([C:16](=[O:24])[NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:11]=[CH:10][C:9]=3[C:8]=2[S:25][C:5]=1[C:3]([OH:4])=[O:2])([OH:30])=[O:29]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)NC3CCCCC3)ccc12
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1c(C(=O)O)sc2c1sc1cc(C(=O)NC3CCCCC3)ccc12
Yield: 69.2 %

Procedure:
Following General Procedure A, 6-cyclohexylcarbamoyl-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (9 mg, 0.02 mmol) was stirred in THF (1 ml) and water (1 ml) for 24 hr. Work-up yielded 6 mg (75%) of title compounds as light yellow solids.
Reaction SMILES: COC([C:5]1([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)=O.CO.[OH-].[K+]>O.Cl>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(c2ncnc3cc(OC)c(OC)cc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Temperature: 100 °C
Yield: 66.7 %

Procedure:
A mixture of crude 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (33 g), as prepared in the previous step, MeOH (100 mL), and KOH pellets (26 g, 400 mmol assuming 87% w/w water) was stirred at reflux (100° C. oil bath) for 1 h, at which point the translucent reddish-amber solution was allowed to cool to rt and diluted with water (100 mL) and 6 M HCl (100 mL). The solution was stirred at 100° C. for 10 min (Caution: Initial vigorous bubbling), allowed to cool to rt, diluted with 2.5 M NaOH (90 mL) and extracted with DCM (1×150 mL; 1×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to afford the title compound as a beige powder (13.95g, 76% from 4-chloro-6,7-dimethoxyquinazoline). 1H-NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 7.48 (s, 1H), 7.32 (s, 1H), 3.98 (s, 3H), 3.96 (s, 3H)m 3.69 (m, 1H), 3.05 (m, 2H), 2.84-2.71 (m, 2H), 1.88-1.65 (m, 4H). LC/MS (ESI): calcd mass 273.2, found 274.2 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]=2[OH:17])=[CH:8][CH:9]=1)=[O:4].[N:18]([O-])=O.[Na+].[CH2:22]1[C:30]2[C:25](=[CH:26][C:27]([N:31]3[C:35](=[O:36])[CH2:34][C:33]([CH3:37])=[N:32]3)=[CH:28][CH:29]=2)[CH2:24][CH2:23]1.C(=O)(O)[O-].[Na+]>Cl>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][N:18]=[C:34]3[C:35](=[O:36])[N:31]([C:27]4[CH:26]=[C:25]5[C:30](=[CH:29][CH:28]=4)[CH2:22][CH2:23][CH2:24]5)[N:32]=[C:33]3[CH3:37])[C:11]=2[OH:17])=[CH:8][CH:9]=1)=[O:4]
Reactant: CC1=NN(c2ccc3c(c2)CCC3)C(=O)C1
Reactant: COC(=O)c1ccc(-c2cccc(N)c2O)o1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(-c2cccc(NN=C3C(=O)N(c4ccc5c(c4)CCC5)N=C3C)c2O)o1
Yield: 69.5 %

Procedure:
5-(3-Amino-2-hydroxy-phenyl)-furan-2-carboxylic acid methyl ester 54c (110 mg, 0.47 mmol) was dissolved in hydrochloric acid (1.6 mL, 1 mol/L) upon cooling by an ice-water bath, followed by dropwise addition of 0.6 mL of aqueous sodium nitrite (36 mg, 0.52 mmol). After the mixture was reacted for 20 minutes, 2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 1i (91 mg, 0.43 mmol) was added. The mixture was adjusted to pH 8˜9 with saturated aqueous sodium bicarbonate. The reaction mixture was reacted at room temperature for 24 hours. The reaction was monitored by TLC until the disappearance of the starting materials and quenched with ethanol. The mixture was filtered and the filter cake was dissolved in 15 mL of water. The mixture was adjusted to pH 3-4 with concentrated hydrochloric acid upon cooling by an ice-water bath. The mixture was filtered and the filter cake was purified by silica gel column chromatography to obtain the title compound 5-{2-hydroxy-3-[N′-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene)-hydrazino]-phenyl}-furan-2-carboxylic acid methyl ester 55 (137 mg, yield 70.3%) as a red solid.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][N:5](C2CCCCO2)[C:4](=[O:14])[CH:3]=1.[CH3:15][N:16]1[C:20](=[O:21])[CH2:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]1.C[O:27][C:28](=[O:37])[CH:29](Br)[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([CH2:30][CH:29]([N:5]2[C:4](=[O:14])[CH:3]=[C:2]([O:21][C:20]3[N:16]([CH3:15])[N:17]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:19]=3)[CH:7]=[N:6]2)[C:28]([OH:27])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1cc(I)cnn1C1CCCCO1
Reactant: CN1N=C(C(F)(F)F)CC1=O
Product: Cn1nc(C(F)(F)F)cc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 70, starting from 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 70, step 2) and 2-methyl-5-trifluoromethyl-2,4-dihydro-pyrazol-3-one and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid as a white solid (4.3 g, 64% for the final step); LC-MS: 401.1 (M+1)+, tR=4.39 min. Purity on HPLC: 97.0% (214 nm), 99.8% (254 nm), tR=9.36 min. 1H NMR (300 MHz, CDCl3): δ 9.00 (s, 1H), 7.91 (d, 1H), 6.46 (d, 1H, J=2.1 Hz), 6.27 (s, 1H), 5.55 (dd, 1H, J1=7.8 Hz, J2=4.2 Hz,), 3.81 (s, 3H), 2.36˜2.20 (m, 1H), 2.20˜2.05 (m, 1H), 1.78˜1.47 (m, 7H), 1.28˜1.10 (m, 2H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[Br:24])(=[O:3])[CH3:2].[NH2:25][C:26]([NH2:28])=[S:27]>CC(C)=O>[BrH:24].[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[S:27][C:26](=[NH:25])[NH2:28])(=[O:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(C)=O
Product: Br
Product: CC(=O)OC[C@H]1O[C@H](SC(=N)N)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
2-S-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl bromide (38 g) dissolved in acetone (180 ml) with thiourea (11 g) at 25° C. Batch heated to reflux for a minimum of 2 hrs. Reaction followed by TLC (1:1 petrol/EtOAc. Starting material 0.69, plus multiple peaks below. Product is a salt and therefore is seen on baseline (uv-active)). Batch cooled to R.T. and crystallised, as a white crystalline solid, with the aid of petrol as an anti-solvent (22 g, 49%). M.p=125-127° C. (Lit6 125-128° c.). [α]D22+101 (CHCl3, C=1.1) (Lit6+103). 1HNMR (400 MHz, DMSO). δ=2.0, 2.0, 2.0, 2.0 (sx4, 3H x4, —C(O)CH3×4), 4.1 (dd, J6,612.4 Hz, J5,62.3 Hz, 1H, H-6), 4.2 (dd, J6,612.4 Hz, J5,65.3 Hz, 1H, H-6′), 4.3 (m, 1H, H-5), 5.1 (dd, J3,410 Hz, J2,33.5 Hz, 1H, H-3), 5.2 (t, J3,49.9 Hz, 1H, H-4), 5.4 (dd, J2,33.4 Hz, J1,21.6 Hz, 1H, H-2), 6.3 (d, J1.3 Hz, 1H, H-1), 9.3 (s, 4H, 2×NH2).
Reaction SMILES: [C:1]1([S:7][CH2:8][Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([Sn:14](Cl)([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13].[Cl-].[NH4+]>CCCCCC.C1COCC1.C1COCC1>[C:1]1([S:7][CH2:8][Sn:14]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: [Li]CSc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)CSc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Using the apparatus and procedure of Example I, 100 ml. of an approximately one-molar solution of (phenylthio) methyllithium in hexane-THF solvent was added dropwise with stirring to 0.1 mole of tributyltin chloride dissolved in THF. The temperature was maintained by means of an ice bath in the range of from 0° C to 20 C. Following the complete addition over a one-half hour period, the reaction mixture was stirred for 1.5 hours at room temperature and hydrolyzed by pouring into aqueous one-molar ammonium chloride. Extraction from the hydrolyzate with ether solvent and purification by vacuum distillation yielded the desired product, (phenylthiomethyl) tributyltin, b.p. 152°-157° C (0.09 mm). Infrared and proton nuclear magnetic resonance spectral analyses confirmed the assigned structure.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][O:19][CH2:20][CH2:21][N:14]3[C@H:13]3[CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][C@@H:12]23)[CH:17]=1.[OH-].[NH4+]>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:8][C:9]2[CH:10]=[C:11]3[C:15]4=[C:16]([CH2:18][O:19][CH2:20][CH2:21][N:14]4[C@H:13]4[CH2:22][CH2:23][NH:24][CH2:25][C@@H:12]34)[CH:17]=2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Agent: [NH4+]
Agent: [OH-]
Product: c1cncc(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c1

Procedure:
Using 3-bromopyridine and following the procedures described in EXAMPLE 56, Part C, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into (7bR,11aS)-N-(3-pyridinyl)-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-amine, bis-trifluoroacetic acid salt. This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 115. LRMS (ES)+: 323.4 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:25][CH2:26][C:27](O)=[O:28])([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[O:14][C:13]2=[O:30])[CH3:11])=[CH:6][CH:5]=1.C[N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C.C1COCC1>[F:1][CH:2]([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:25][CH2:26][C:27]([NH2:33])=[O:28])([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[O:14][C:13]2=[O:30])[CH3:11])=[CH:6][CH:5]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@@H](c1ccc(OC(F)F)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(OC(F)F)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 49 %

Procedure:
To a solution of 3-((R)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid (0.0485 g, 0.11 mmol) in DMF (2 mL) was added HATU (0.2603 g, 0.68 mmol), DIPEA (0.5 mL), and 0.8 M NH3 in THF (3 mL). The mixture was stirred at rt for 22 h. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0235 g (49%) of 3-((R)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide. LC-MS Method 1 tR=1.48 min, m/z 459 (MNa+), 393; 1H NMR (400 MHz, CDCl3) δ 7.23-7.20 (m, 2H), 7.04-6.99 (m, 2H), 6.95 (d, J=8.2 Hz, 2H), 6.89 (d, J=8.5 Hz, 2H), 6.43 (t, J=73.8 Hz, 1H), 5.83-5.78 (m, 2H), 5.62 (q, J=7.0 Hz, 1H), 2.95-2.91 (m, 1H), 2.45 (m, 1H), 2.27-2.15 (m, 5H), 1.98 (m, 1H), 1.49 (d, J=7.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −81.51 (d, J=73.7 Hz), −114.66 (m).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=2)[CH2:24][CH2:25]1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccccn3)CC2)cc1
Yield: 152.3 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.0 g), 1-(2-pyridyl)piperazine (1.4 g) and potassium carbonate (4.2 g) in dimethylformamide (20 ml) was stirred at 60-70° C. for 2.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil. The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give a pale-yellow oil (2.5 g). The obtained pale-yellow oil was crystallized from ethyl acetate and the crystals were recrystallized from ethyl acetate to give the title compound (1.4 g) as white crystals, m.p.=100-101° C.
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]3[CH2:31][CH2:30][N:29](C)[CH2:28][CH2:27]3)=[N:18]2)=[CH:13][CH:12]=1.O>CS(C)=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]3[CH2:31][CH2:30][N:29]([C:2]#[N:1])[CH2:28][CH2:27]3)=[N:18]2)=[CH:13][CH:12]=1
Reactant: N#CBr
Reactant: CN1CCC(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CN1CCC(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 104 %

Procedure:
To a stirred mixture of cyanogen bromide (21.67 g, 0.204 moles) and potassium carbonate (33.2 g, 0.24 moles) in dimethyl sulfoxide (400 ml) was added dropwise a solution of 1-(4-fluorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole (59.45 g, 0.192 moles), the free base of example 67, in hot dimethyl sulfoxide (375 ml). The reaction was stirred at ambient temperature for 4 days and then poured into H2O (500 ml). The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 64 g of a solid. The product was recrystallized twice from isopropyl alcohol yield 35.7 g (58%) of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile, mp 108°-110° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:13]([CH:14]=[O:15])=[C:12](Br)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([F:28])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.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>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:6](=[O:17])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]=2[CH:14]=[O:15])=[C:21]([F:28])[CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)Nc1nccc(Br)c1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nccc(-c2ccc(Cl)cc2F)c1C=O
Temperature: 85 °C
Yield: 51.5 %

Procedure:
To a stirred suspension of tert-butyl(4-bromo-3-formylpyridin-2-yl)carbamate (100 mg, 0.332 mmol), (4-chloro-2-fluorophenyl)boronic acid (57.9 mg, 0.332 mmol) and cesium carbonate (216 mg, 0.664 mmol) in THF (50 mL) and water (8 ml) was added Pd(PPh3)4 (19.19 mg, 0.017 mmol) and the reaction mixture was heated to 85° C. overnight. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (1×25 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (ethyl acetate/hexanes) to afford tert-butyl 4-(4-chloro-2-fluorophenyl)-3-formylpyridin-2-ylcarbamate (60 mg, 0.171 mmol, 35% yield). LCMS (ESI) m/e 349.2 [(M−H)−, calcd for C17H15ClFN2O3 349.1]; LC/MS retention time (Method C): tR=2.05 min.
Reaction SMILES: C(O)C.[OH-].[Na+].[CH3:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl>O.C1COCC1>[CH3:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(COC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Ethanol (20 mL) and a 2.0 mol/L aqueous solution (10 mL) of sodium hydroxide were added to a THF (20 mL) solution of ethyl 4′-(methoxymethyl)biphenyl-4-carboxylate (3.5 g) as obtained in Example 3-(2), and the mixture was stirred for 1 hour at 80° C. Water was added to the reaction mixture, and the mixture was neutralized with an aqueous solution of hydrochloric acid. Then, the precipitate was collected by filtration to obtain 4′-(methoxymethyl)biphenyl-4-carboxylic acid (gray solid) (3.0 g, 96%).