Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4]1)C.[Br:15]N1C(=O)CCC1=O>>[Br:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[N:7][N:3]([CH3:1])[N:4]=2)=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1nnc(-c2ccc(C)cc2)n1
Product: Cn1nnc(-c2ccc(CBr)cc2)n1

Procedure:
As depicted in Scheme 5, Intermediate (M), for example, 5-(4-methylphenyl)-1,2,3,4-tetraazole, was prepared by reacting an appropriate toluonitrile, for example para-toluonitrile, with sodium azide at elevated temperature in an appropriate solvent. Intermediate (M) was then alkylated with an appropriate iodoalkane under basic conditions, affording the corresponding alkylated tetraazole (N), for example, 2-ethyl-5-(4-methylphenyl)-1,2,3,4-tetraazole. Intermediate (N) was in turn brominated with, for example, N-bromosuccinimide at elevated temperature in an appropriate solvent, providing the corresponding bromomethyl derivative (O), for example, 5-[4-(bromomethyl)phenyl]-2-ethyl-1,2,3,4-tetraazole. Intermediate (O) was then reacted with ethyl isonipecotate under basic conditions in an appropriate solvent, providing the corresponding ester (P), for example, ethyl 1-{[4-(2-ethyl-1,2,3,4-tetraazol-5-yl)phenyl]methyl}piperidine-4-carboxylate, which was in turn converted to its piperidinecarboxylic acid (Q) by reacting it with aqueous sodium hydroxide in an appropriate solvent, affording, for example, 1-{[4-(2-ethyl-1,2,3,4-tetraazol-5-yl)phenyl]methyl}piperidinecarboxylic acid. Intermediate (Q) was then reacted with, for example, N,O-dimethylhydroxylamine hydrochloride and diethylcyanophosphonate, under basic conditions at reduced temperature in an appropriate solvent, yielding the corresponding piperidine carboxamine (R), for example, 1-{[4-(2-ethyl(1,2,3,4-tetraazol-5-yl))phenyl]methyl}(4-piperidyl)-N-methoxy-N-methylcarboxamide. Intermediate (R) was reacted with a Grignard Reagent, for example, 4-trifluoromethoxyphenylmagnesium bromide, in an appropriate solvent, affording the corresponding ketone (S), for example, 1-{[4-(2-ethyl(1,2,3,4-tetraazol-5-yl))phenyl]methyl}(4-piperidyl)4-(trifluoromethoxy)-phenyl ketone. The ketone (S) is then halogenated with, for example, phosphorous oxychloride in an appropriate solvent, yielding the corresponding halogen compound (S1), for example, {4-[chloro(1-{[4-(2-ethyl(1,2,3,4-tetraazol-5-yl))phenyl]methyl}(4-piperidyl))methyl]phenoxy}trifluoromethane. Intermediate (S1) is in turn reacted with, for example, an appropriate phenol, such as 4-(trifluoromethoxy)phenol in an appropriate solvent, providing the corresponding phenoxy derivative, a compound of formula I, for example, 1-[(1-[[4-(2-ethyl(1,2,3,4-tetraazol-5-yl))phenyl]methyl}(4-piperidylidene))[4-(trifluoromethoxy)phenyl]methoxy]-4-(trifluoromethoxy)benzene. Example 11, set forth below provides a detailed procedure for this synthesis.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([O:14][CH:15]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH:15]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:27][CH:28]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1)Oc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.8 %

Procedure:
To a solution of 0.520 g (1.30 mmol) of the product of Step C dissolved in 3 mL of anhydrous THF was added 1.3 mL (1.3 mmol) of a 1N solution of tetra-n-butylammonium fluoride in THF and the mixture was stirred at room temperature 1.5 hours. The mixture was then concentrated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 70% ethyl acetate/hexane to afford 0.230 g (62%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[Na+].[I-].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:31]([O:38][C:39]1[CH:44]=[C:43](I)[CH:42]=[CH:41][C:40]=1[N:46]1[S:50](=[O:52])(=[O:51])[N:49]([CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:48](=[O:59])[CH2:47]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:31]([O:38][C:39]1[CH:44]=[C:43]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH:42]=[CH:41][C:40]=1[N:46]1[CH2:47][C:48](=[O:59])[N:49]([CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[S:50]1(=[O:52])=[O:51])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N#CCCCBr
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCCC#N)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-bromobutyronitrile (0.074 mL, 0.75 mmol) in DMF (2 mL) is added Rieke zinc (0.9 mmol) and a catalytic amount of NaI. The mixture is stirred at RT for 5 h then P(o-tolyl)3 (22.8 mg, 15 mol %), Pd2(dba)3 (13.7 mg, 3 mol %) and 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (272 mg, 0.5 mmol) is added and the mixture is stirred at RT for 18 h. The mixture is partitioned between EtOAc and 1N HCl and the organic phase is washed with brine and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using a gradient of 0-15% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: O=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH:4]2[CH2:3]1.B.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.ClCCl.CO>[CH2:13]1[N:5]2[C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[NH:8][CH2:2][CH2:3][CH:4]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2c3ccccc3NCCC2C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 1C (1 g, 3.15 mmol) in tetrahydrofuran (10 mL) was added borane (1M/tetrahydrofuran, 12.6 mL, 12.6 mmol). The solution was heated to 80° C. for 4 hours. Methanol (20 mL) was added, and the reaction heated at 80° C. for 1 hour. The reaction was cooled to room temperature and 1M HCl (30 mL) was added. This solution was stirred for 30 minutes, before the solution was neutralized with sodium bicarbonate (aqueous). Dichloromethane was used to extract the product. The product was purified via flash chromatography (20-70% ethyl acetate/hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.77 (d, J=7.54 Hz, 1H), 6.64-6.73 (m, 1H), 6.48-6.59 (m, 2H), 5.27 (s, 1H), 3.54-3.67 (m, 1H), 3.35-3.50 (m, 2H), 3.20-3.29 (m, 1H), 2.96-3.19 (m, 4H), 2.85-2.96 (m, 1H), 1.76-1.92 (m, 1H), 1.59-1.75 (m, 1H), 1.41 (s, 9H); MS (APCI+) m/z 304.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6](=O)[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.C([O-])(=O)C.[Na+].[CH3:24][O:25][NH3+:26].[Cl-]>CO>[CH3:24][O:25]/[N:26]=[C:6]1/[C:2]([CH3:18])([CH3:1])[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]/1
Reactant: CO[NH3+]
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CC1=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CO/N=C1\CN(C(=O)OCc2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
To a solution of benzyl 3,3-dimethyl-4-oxopyrrolidine-1-carboxylate (2.91 g, 11.8 mmol) in MeOH (10 mL) was added sodium acetate (1.93 g, 23.5 mmol) and o-methylhydroxylamine hydrochloride (1.97 g, 23.5 mmol). The mixture was stirred at rt for 18 h. The reaction was concentrated and then diluted with dichloromethane (200 mL). The organic layer was washed with water (20 mL) and aq. sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. (Z)-benzyl 4-(methoxyimino)-3,3-dimethylpyrrolidine-1-carboxylate (3.17 g, 97% yield) was obtained as a colorless oil. m/z: 277.17 (M+H); LC retention time: 2.83 min (analytical HPLC Method I).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5].[CH3:16][Mg]Br.O.[Cl-].[NH4+]>O1CCCC1>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:4](=[O:5])[CH3:16])=[N:7]1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1n[nH]c2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1n[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 20 h

Procedure:
In a round-bottomed flask, 2.4 g of N-methoxy-N-methyl-1H-indazole-3-carboxamide are placed in 140 ml of tetrahydrofuran at 0° C. and under argon. 19 ml of methylmagnesium bromide (3M in ethyl ether) are added dropwise. The mixture is stirred for one hour at 0° C. and 20 h at ambient temperature. It is cooled to 0° C. and 80 ml of water and 40 ml of a saturated solution of ammonium chloride are added. The mixture is extracted with 40 ml of ethyl acetate. The organic phase is washed with 40 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 1.6 g of compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:16][CH3:17].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:27]=2[O:35][CH3:36])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:33])[CH3:34])=[CH:28][C:27]=2[O:35][CH3:36])=[N:24][C:19]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:16][CH3:17])=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Reactant: COc1cc(N(C)C)ccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccc(N(C)C)cc3OC)n1)c2OC
Yield: 65.3 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (64 mgs) and N(1)-(2,5-Dichloro-pyrimidin-4-yl)-2-methoxy-N(4),N(4)-dimethyl-benzene-1,4-diamine (77 mgs) were converted to the title compound (82 mgs) as a white solid. 1H-NMR (CDCl3, 400 MHz): 8.29 (d, J=8.2 Hz, 1H), 8.09-8.04 (m, 2H), 7.42 (s, 1H), 7.38 (s, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.39-6.37 (m, 2H), 4.31-4.10 (broad absorption, 2H), 3.93 (s, 3H), 3.84 (s, 6H), 3.00-1.95 (broad absorption, 6H), 1.16 (t, J=7.0 Hz, 3H); LC/MS: found (M+H)+=511.46 MP: 190-193° C.;
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:42]1[CH2:43][CH2:44][N:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:40][CH2:41]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2ccccc2)CC1
Yield: 9.5 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-phenyl-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (6.3 mg, 9.5%) as light yellow oil. MS m/e=491.4 [M+H]+.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[NH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].ON1C2C=CC=CC=2N=N1.CN(C)CCCCN=C=NCC.CN1CCOCC1>ClCCl.O>[CH2:4]([O:3][C:1]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=[O:19])[NH:21][CH2:22][C:23](=[O:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NCC(=O)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CNC(=O)C1CCCCN1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
(S)-1-(Carbobenzyloxy)-2-piperidinecarboxylic acid (15.8 g, 60 mmol), 2-amino-1phenyl-ethanone hydrochloride (10.30 g, 60 mmol), and HOBT (1-hydroxybenzo-triazole) (16.20 g, 120 mmol) were mixed in dichloromethane (400 mL). The stirring mixture was cooled to 0° C. and then (4-dimethylamino-butyl)-ethyl-carbodiimide (14.90 g, 78 mmol) and NMM (N-methyl-morpholine) (7.27 g, 72 mmol) were added. The reaction mixture was then warmed to room temperature. After 16 hours the reaction mixture was treated with water, and the resulting solid was filtered. The organic phase from the filtrate was separated and washed consecutively with saturated NaHCO3, 2N citric acid, and saturated NaHCO3 once again, then dried over MgSO4, filtered, and concentrated to yield the title product 2-(2-oxo-2-phenyl-ethylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester as a yellow oil, which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([OH:17])=O)=[N:13][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[C@H:18]12[CH2:24][C@H:21]([NH:22][CH2:23]1)[CH2:20][N:19]2[C:25]([C@@H:27]([NH:32][C:33]([C:35]1[NH:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.O.C([O-])([O-])=O.[Na+].[Na+]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:22]3[CH2:23][C@@H:18]4[CH2:24][C@H:21]3[CH2:20][N:19]4[C:25]([C@@H:27]([NH:32][C:33]([C:35]3[NH:36][C:37]4[C:42]([CH:43]=3)=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:17])=[N:13][CH:14]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(C(=O)O)nc2)cc1
Reactant: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2ccc(C#N)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a 200 ml flask was added 5-(4-cyanophenyl)-2-pyridinecarboxylic acid (0.76 g, 3.39 mmol), N-{(1S)-1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-2,2-dimethylpropyl}-1H-indole-2-carboxamide (1 g, 2.82 mmol), EDC (1.30 g, 6.77 mmol), HOBt (0.52 g, 3.39 mmol), CH2Cl2 (28 ml), DIEA (1.971 ml, 11.29 mmol). The mixture was stirred at room temperature overnight then diluted with CH2Cl2, water and sat. Na2CO3. The two layers were separated and the organic washed with 2N HCl, sat. NaHCO3 and brine. The CH2Cl2 was passed over a phase separator and concentrated to afford a brown residue. The residue was purified by reverse phase chromatography on a Biotage SP4 with a 65i column at a flow rate of 65 ml/min, 0.1% TFA eluting with 2CV water, the 0-100% ACN/Water over 20 CV. The fractions containing the product were combined and diluted with CH2Cl2 and sat. NaHCO3. The layers were separated and the CH2Cl2 was dried and concentrated to afford the desired product (1.0 g, 1.75 mmol) as an off white solid. LCMS (m/z): 561.3 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (s, 1H), 1.02-1.07 (m, 4H), 1.10 (s, 4H), 1.74-2.12 (m, 2H), 3.37-4.03 (m, 4H), 4.55-5.26 (m, 3H), 6.87-7.24 (m, 2H), 7.26-7.68 (m, 3H), 7.78-8.41 (m, 7H), 8.48-9.18 (m, 1H), 11.52-11.87 (m, 1H).
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[CH3:16].[C:17](=[O:19])=[O:18]>C1COCC1>[CH3:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:17]([OH:19])=[O:18])[CH:8]=2)[NH:12][N:11]=1
Reactant: O=C=O
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
A three necked round bottom flask equipped with an internal thermometer and an overhead stir motor was charged with 600 mL of THF and chilled to −78° C. t-BuLi (1.7 M in THF, 200 mL, 0.340 mol) was added to the flask, and the mixture was stirred for 15 minutes. 5-Bromo-3-methyl-1H-indazole (22.4 g, 0.106 mol) in 200 mL THF was then added dropwise via an addition funnel. The rate of addition was closely monitored to make sure that the internal temperature remained below −70° C. The resulting orange solution was stirred for 30 minutes, at which point CO2 was bubbled through the mixture. A white precipitate was observed. After 20 minutes, the ice bath was removed and the temperature was allowed to warm to room temperature. The resulting mixture was stirred for an additional 30 minutes. Water was then added to the mixture (40 mL initially followed by a further 200 mL). The biphasic mixture was partially concentrated under reduced pressure, removing about 75% of the original organic portion. The biphasic solution was then transferred to an addition funnel, and the organic phase was extracted with 100 mL of 2M NaOH. The combined aqueous extracts were washed with ether and then acidified to pH=2.0 with concentrated HCl. A precipitate began to form, and the mixture was cooled to 0° C. to complete the precipitation. The resulting solid was filtered, washed with 1M HCl, and dried under reduced pressure at 160° C. over phosphorus pentoxide, affording 3-methyl-1H-indazole-5-carboxylic acid (18.1 g, 96% yield) as a pink/beige solid. LCMS (API-ES) m/z (%): 177.0 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 2.61 (s, 3H) 3.33 (b, 2H), 7.52 (d, J=6.0 Hz, 1H), 8.05 (d, J=6.0 Hz, 1H), 8.50 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]O.C(N(CC)C(C)C)(C)C.S(Cl)([Cl:26])=O>C(OCC)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][Cl:26]
Reactant: COCOc1c(CO)cccc1OC
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(CCl)cccc1OC
Reaction time: 0.25 h

Procedure:
2.34 g (11.8 mmol) of 2-methoxymethoxy-3-methoxybenzyl alcohol was dissolved in 20 ml of diethyl ether, and the resultant solution was added with 1.53 g (11.8, mmol) of N,N-diisopropylethylamine. To the obtained solution was fed dropwise 1.40 g (11.8 mmol) of thionyl chloride and diethyl ether (15 ml) in a manner of spending 15 min. while cooling the solution with ice. The temperature of the resultant mixture was then brought back to a room temperature, and the mixture was stirred all night. The insoluble materials therein are removed by filtration, and the filtrate was condensed under reduced pressure to thereby obtain a crude product of 2-methoxymethoxy-3-methoxybenzyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O>[CH2:11]([S:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[CH3:12]
Reactant: Sc1cc(Cl)cc(Cl)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCSc1cc(Cl)cc(Cl)c1
Yield: 97.1 %

Procedure:
A solution of 3,5-dichlorobenzenethiol (1.50 g, 8.4 mmol), iodoethane (1.34 mL, 16.8 mmol), potassium carbonate (1.74 g, 12.6 mmol) and methylene chloride (10 mL) was stirred at 25° C. for 30 minutes. The reaction was diluted with water and extracted with ethyl acetate three times, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel to give the desired product (1.69 g, 97%). LC/MS: 207 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][C:22]#[N:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:24](=[O:29])[C@@H:25]([O:27][CH3:28])[CH3:26])[N:10]=1.Cl.Cl.[O:32]([NH2:34])[CH3:33].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][C:22](=[N:34][O:32][CH3:33])[NH2:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:24](=[O:29])[C@@H:25]([O:27][CH3:28])[CH3:26])[N:10]=1
Reactant: CON
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCC#N)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CON=C(N)CCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 25 %

Procedure:
To cooled (0° C.) solution of 3-(5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propanenitrile (0.052 g, 0.13 mmol, Example 14, Step C) in ethanol (0.5 mL) was added 9.8 M ethanolic HCl (0.5 mL, 4.9 mmol). After stirring at room temperature for 6 hours, the mixture was concentrated under reduced pressure. To the residue was added methoxylamine hydrochloride (0.021 g, 0.21 mmol), absolute ethanol (0.5 mL) and triethylamine (0.087 mL, 0.63 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure. The residue was diluted with 10% Na2CO3 (30 mL) and extracted with dichloromethane. The combined organics were dried, filtered and concentrated under reduced pressure. The residue was chromatographed (40% ethyl acetate in hexanes) to afford the product as a mixture of diastereomers (14 mg, 25% yield). MS ESI (+) m/z 463 (M+1) detected; 1H NMR (4001 MHz, CDCl3) δ 7.50 (m, 2H), 7.38 (m, 8H), 7.30 (m, 2H), 7.13 (m, 4H), 4.78 (q, 1H, J=6.3 Hz), 4.72 (q, 1H, J=6.3 Hz), 4.64 (br. s, 4H), 3.77 (s, 6H), 3.54 (m, 2H), 3.41 (s, 3H), 3.36 (s, 3H), 2.68 (m, 4H), 2.18 (m, 2H), 1.51 (d, 3H, J=6.3 Hz), 1.49 (d, 3H, J=7.0 Hz).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=O)[C:12]([OH:14])=[O:13].[C:16]([O:20][C:21]([CH2:23][O:24][NH2:25])=[O:22])([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+]>O.N1C=CC=CC=1.O1CCCC1>[C:16]([O:20][C:21]([CH2:23][O:24][N:25]=[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:12]([OH:14])=[O:13])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CON
Reactant: O=C(O)C(=O)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1ccc2ccccc2c1
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 2-naphthylglyoxylic acid (6 g) in water (60 ml) and pyridine (6 ml) was added tert-butoxycarbonylmethoxyamine (9 g) in tetrahydrofuran (40 l) at room temperature and the mixture was stirred at the same temperature for 3 hours. The resultant mixture was adjusted to pH 7.5 with 10% aqueous sodium hydroxide and washed with ethyl acetate. The aqueous layer was acidified to pH 2.0 with 10% hydrochloric acid and the acidified solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solution was evaporated in vacuo to give 2-(tert-butoxycarbonylmethoxyimino)-2-(2-naphthyl)acetic acid (syn isomer) (8 g).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:15]([F:16])=[CH:14][C:13](Br)=[CH:12][C:11]=2[F:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[C:1]1([S:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:22]3[CH:21]=[C:20]([Cl:19])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])=[CH:12][C:11]=2[F:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1c(F)cc(Br)cc1F
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1-c1cc(F)c(S(=O)(=O)c2ccccc2)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-chloro-2-methoxybenzene boronic acid which was used directly in step (iv) without further characterisation.