Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=O.[Cl:8][C:9]1[C:10](=[N:15][NH2:16])[NH:11][CH:12]=[CH:13][CH:14]=1>>[F:1][C:2]([F:7])([F:6])[C:3](=[N:16][N:15]=[C:10]1[C:9]([Cl:8])=[CH:14][CH:13]=[CH:12][NH:11]1)[CH3:5]
Reactant: CC(=O)C(F)(F)F
Reactant: NN=c1[nH]cccc1Cl
Agent: NNc1ncccc1Cl
Product: CC(=NN=c1[nH]cccc1Cl)C(F)(F)F
Reaction time: 0.17 h
Yield: 66 %

Procedure:
1,1,1-Trifluoroacetone (7.80 g, 69.6 mmol) was added to 3-chloro-2(1H)-pyridinone hydrazone (alternatively named (3-chloro-pyridin-2-yl)-hydrazine) (10 g, 69.7 mmol) at 20-25° C. After the addition was complete, the mixture was stirred for about 10 minutes. The solvent was removed under reduced pressure and the mixture partitioned between ethyl acetate (100 mL) and saturated aqueous sodium carbonate solution (100 mL). The organic layer was dried and evaporated. Chromatography on silica gel (eluted with ethyl acetate) gave the product as an off-white solid (11 g, 66% yield), m.p. 64-64.5° C. (after crystallization from ethyl acetate/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22](COCC[Si](C)(C)C)[C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][CH:39]([CH2:40][C:41](N)=[O:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(Cl)Cl>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][CH:39]([CH2:40][CH2:41][OH:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@@H]3C(CC(N)=O)CO[C@@H]32)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCCC1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1

Procedure:
2-[(3aR,6R,6aS)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]acetamide (84.6 mg, 0.139 mmol) was dissolved in TFA (0.5 mL) and DCM (1.0 mL) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was then evaporated to an oil, dissolved in methanol (0.5 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient. The desired fractions were lyophilized to give the title compound as a solid. Major isomer LC-MS: calculated for C26H24ClN3O4 477.15 observed m/e: 478.26 (M+H)+ (Rt 1.10/2 min); 1H NMR δ (ppm) (CD3OD): 7.87 (s, 1H), 7.75 (ABq, 4H), 7.71 (d, 2H), 7.48 (dd, 2H), 7.38 (dd, 1H), 5.56 (qt, 1H), 4.98 (t, 1H), 4.53 (t, 1H), 4.10 (dd, 1H), 4.04-3.96 (m, 3H), 3.63 (t, 2H), 3.54 (dd, 1H), 2.34 (m, 2H), 1.95 (m, 2H) and 1.77 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:27]1([CH2:33][CH:34]2[CH:39]([NH2:40])[CH:38]3[CH2:41][CH2:42][N:35]2[CH2:36][CH2:37]3)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:40][CH:39]1[CH:38]2[CH2:37][CH2:36][N:35]([CH2:42][CH2:41]2)[CH:34]1[CH2:33][N:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:9]
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Reactant: NC1C2CCN(CC2)C1CN1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CNc1cc(OC)c(C(=O)NC2C3CCN(CC3)C2CN2CCCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.5 %

Procedure:
A solution of 5-chloro-2-methoxy-4-(methylamino)-benzoic acid (1.95 g, 9.0 mmoles) in anhydrous tetrahydrofuran (10 ml) was treated with 1,1'-carbonyldiimidazole (1.49 g, 9.2 mmoles), stirred at room temperature for 90 minutes, then added to a cooled (0° C.) solution of 2-(1-piperidylmethyl)-1-azabicyclo[2.2.2]octan-3-amine (2.12 g, 9.5 mmoles) in anhydrous tetrahydrofuran (10 ml) under nitrogen. After 18 hours at room temperature the solution was concentrated in vacuo and partitioned between methylene chloride (100 ml) and 1.0N sodium hydroxide (40 ml). The organic solution was separated and washed with 1.0N sodium hydroxide (40 ml), saturated aqueous sodium bicarbonate (40 ml), and brine (40 ml), dried (Na2SO4), and concentrated in vacuo. Filtration through alumina (eluted with 15% methanol/ethyl acetate) provided 3.24 g (86%) of a colorless foam.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C1NCCCn2c1cc1cc(F)cc(-c3ccc(Cl)cc3)c12

Procedure:
The title compound, light grey solid (78 mg, 95%), MS (ISP) m/z=329.2 [(M+H)+], mp 263.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [Na:1].S(CCC[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]CS(O)(=O)=O)=[CH:13][CH:12]=1)(O)(=O)=O.COC1C=CC(O)=CC=1.C1[S:40](=[O:42])(=[O:41])[O:39]CCC1.[Na].COC1C=CC=CC=1OCCCCS(O)(=O)=O>>[Na:1].[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][S:40]([OH:42])(=[O:41])=[O:39])=[CH:15][CH:16]=1
Reactant: O=S(=O)(O)CCCCOc1ccc(OCCCCS(=O)(=O)O)cc1
Reactant: O=S1(=O)CCCCO1
Agent: COc1ccc(O)cc1
Agent: COc1ccccc1OCCCCS(=O)(=O)O
Agent: [Na]
Product: COc1ccc(OCCCS(=O)(=O)O)cc1

Procedure:
In the same manner as in above (1), the objective compound was synthesized from 4-methoxyphenol and butanesultone. The crude product was recrystallized from water to obtain a milky white needle crystal product. The resulting product was determined for its 1H-NMR and IR spectrum to confirm that it was 1-methoxy-4-sulfobutoxybenzene sodium.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.FC(F)(F)C([NH:48][C@@H:49]1[CH2:53][CH2:52][NH:51][CH2:50]1)=O>CS(C)=O.COC(C)(C)C>[NH2:48][C@@H:49]1[CH2:53][CH2:52][N:51]([C:21]2[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)([CH3:34])[CH3:33])=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])[CH:22]=2)[CH2:50]1
Reactant: O=C(N[C@@H]1CCNC1)C(F)(F)F
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@@H](N)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 52 h
Yield: 65.3 %

Procedure:
A mixture of 939 mg (1.76 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 1.22 g (8.81 mmol) potassium carbonate and 770 mg (3.52 mmol) (R)-3-(trifluoro-acetamido)pyrrolidine hydrochloride in 20 ml dimethyl sulfoxide was stirred at 130° C. for 52 h. After cooling to room temperature the reaction mixture was diluted with 30 ml tert-butyl methyl ether and washed with 20 ml of water and 10 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and dissolved in 25 ml of a 2 N solution of ammonia in ethanol. The solution was stirred at room temperature for 18 h. The reaction mixture was concentrated and purified by flash chromatography to give 670 mg (65%) of the title compound as a light brown foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:19][CH2:18]1.O>>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:22][CH2:21]1
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Reactant: O=C1CCCc2c(O)cccc21
Solvent: O
Product: COc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3=O)CC1
Yield: 78.8 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine; yield 78.8% of theory; the hydrochloride, after recrystallization from water and drying, contained 0.486 mol water; m.p. 174°-175°C;
Reaction SMILES: Cl[C:2]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].N1C=CC=CC=1>CC1C=CC(C)=CC=1>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[S:25][C:2]2[C:11]([N:12]=1)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)([O-:22])=[O:21]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)c1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Solvent: Cc1ccc(C)cc1
Solvent: c1ccncc1
Product: COC(=O)c1cnc2sc(-c3ccccc3[N+](=O)[O-])nc2c1
Temperature: 130 °C
Yield: 57 %

Procedure:
A mixture of methyl 6-chloro-5-(2-nitrobenzamido)nicotinate (1 eq), P2S5 (2.1 eq), and pyridine (7.6 eq) in p-xylene was heated at 130° C. for 2 h. The clear liquid was decanted and allowed to cool to room temperature. The resultant precipitate was collected by filtration and dried to give methyl 2-(2-nitrophenyl)thiazolo[5,4-b]pyridine-6-carboxylate (57% yield).
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][C:29]=2[CH3:38])[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]1=2)(=[O:3])[CH3:2].[ClH:43]>O1CCOCC1.CCOCC>[ClH:43].[ClH:43].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][C:29]=2[CH3:38])[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2N(Cc2c(C)cnc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)cnc3ccccc23)c2ccccc2N(C(C)=O)[C@H]1C
Yield: 79 %

Procedure:
A rt solution of tert-butyl(S)-1-((2S,3S)-1-acetyl-2-methyl-5-((3-methylquinolin-4-yl)methyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (96 mg, 167 μmol) in 4 M HCl in dioxane (837 μl) was stirred for 1.5 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((2S,3S)-1-acetyl-2-methyl-5-((3-methylquinolin-4-yl)methyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide dihydrochloride (72.2 mg, 79%) as an off-white solid. MS m/z 474 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[N:10]=2)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=1.C([Si](C)(C)[O:44][CH:45]1[CH2:48][CH:47]([N:49]2[CH:53]=[C:52](B3OC(C)(C)C(C)(C)O3)[CH:51]=[N:50]2)[CH2:46]1)(C)(C)C>>[OH:44][CH:45]1[CH2:48][CH:47]([N:49]2[CH:53]=[C:52]([C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9]4[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]5[CH:21]=[CH:22][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:33][CH:34]=5)[N:10]=4)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=3)[CH:51]=[N:50]2)[CH2:46]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Reactant: CC1(C)OB(c2cnn(C3CC(O[Si](C)(C)C(C)(C)C)C3)c2)OC1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C5CC(O)C5)c4)cc3C(=O)NC)n2)cc1)OCC

Procedure:
The title compound was prepared using the procedure from Example 97 with Diethyl (4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and 1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Compound 100A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10].CI.[CH2:14]1CCCCC1>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[NH:11])[S:10][CH3:14]
Reactant: C1CCCCC1
Reactant: NC(=S)Nc1ccccc1F
Solvent: CI
Solvent: CC(C)=O
Product: CSC(=N)Nc1ccccc1F

Procedure:
To a stirred solution of 3.0 g (0.017 mol) of N-(2-fluorophenyl)thiourea in 75 ml of acetone was added an excess of methyl iodide. The reaction was allowed to stir over night. To the solution was then added 20 ml of cyclohexane; a white solid crystallized and was collected by filtration to yield 4.3 g of N-(2-fluorophenyl)-S-methylisothiourea.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]([C:18]3[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=3)=O)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[NH2:26][NH2:27]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]3[C:18]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:27][N:26]=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Solvent: CCO
Solvent: O
Product: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ncccc23)[nH]1
Temperature: 80 °C
Yield: 45 %

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (477 mg, 1.4 mmol) and hydrazine hydrate (2 mL) in ethanol (30 mL) was heated at 80° C. for 24 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 200 mg (45%) of the titled compound.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].NC(N)=O.[C:9]([C:12]([CH2:19]O)([C:16]([OH:18])=[O:17])[C:13]([OH:15])=[O:14])([OH:11])=[O:10].OS(O)(=O)=O>O>[C:16]([C:12]([CH2:19][O:2][N+:1]([O-:4])=[O:3])([C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])([OH:18])=[O:17]
Reactant: O=C(O)C(CO)(C(=O)O)C(=O)O
Reactant: O=[N+]([O-])O
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C(CO[N+](=O)[O-])(C(=O)O)C(=O)O
Yield: 30 %

Procedure:
To a mixture cooled to 0° C. of 2.5 g of 95 (%) strength HNO3, a spatula-full of urea and 10 ml of water is added with stirring and ice-cooling, 1.0 g (0.004 mol) of carboxy-2-hydroxymethylmalonic acid. After 10 min 2.5 g of 94% strength H2SO4 are added dropwise with stirring and stirring is continued for another hour at 0° C. The organic layer is isolated and evaporated down. 2-carboxy-2-nitryloxymethylmalonic acid is obtained as the residue as a viscous oil which is purified column chromatographically.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-(t-butoxycarbonyl)azetidine-3-carboxylic acid (1-1) (AXL016917, 1000 mg, 4.97 mmol) was dissolved in MeOH (5 mL)/Toluene (20 mL) and then cooled to 0° C. TMSCHNN (trimethylsilyldiazomethane) (7.45 mmol) was then added drop-wise over 15 minutes with some bubbling observed. The color started clear and slowly turned yellow. The solution was stirred for 10 minutes at 0° C. and then warmed to room temperature over 30 minutes. The solution was then concentrated and pumped on to remove toluene to afford 1.055 g of 1-t-butyl 3-methyl azetidine-1,3-dicarboxylate (1-2) that was used directly in the next step without being purified (99% crude yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Fc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: Brc1ccc2ccccc2n1
Product: Fc1ccc2c(c1)c1c(n2-c2ccc3ccccc3n2)C2CCN(CC2)C1

Procedure:
The reaction of 9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg, 1.0 mmol; Example 161) and 2-bromoquinoline (312 mg, 1.5 mmol; Alfa Aesar) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.98-2.11 (m, 2H) 2.17-2.31 (m, 2H) 3.09-3.28 (m, 5H) 4.31 (s, 2H) 6.90 (td, J=9, 3 Hz, 1H) 7.13 (dd, J=9, 2 Hz, 1H) 7.42 (dd, J=9, 4 Hz, 1H) 7.57 (d, J=8 Hz, 1H) 7.67 (t, J=8 Hz, 1H) 7.79-7.87 (m, 1H) 7.98-8.08 (m, 2H) 8.55 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4]/[C:5](/[CH3:16])=[CH:6]/[C@@H:7]1[C@@H:9]([C:10]([O:12]C)=[O:11])[C:8]1([CH3:15])[CH3:14].[OH-].[Na+].CO>O>[CH3:1][O:2][N:3]=[CH:4]/[C:5](/[CH3:16])=[CH:6]/[C@@H:7]1[C@@H:9]([C:10]([OH:12])=[O:11])[C:8]1([CH3:15])[CH3:14]
Reactant: CON=C/C(C)=C/[C@@H]1[C@@H](C(=O)OC)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CON=C/C(C)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
Under nitrogen atmosphere, a mixture of 0.57 g of methyl (1R)-trans-3-[(E)-3-methoxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate, 7.5 ml of 1 mol/L sodium hydroxide aqueous solution and 7.5 ml of methanol was stirred at 60° C. for 3 hours. Then, water was added to the reaction mixture, and the mixture was washed with diethyl ether. 1 mol/L hydrochloric acid was added to the resultant aqueous layer to make the layer acidic, and extraction with diethyl ether was performed, then, the organic layer was dried over anhydrous magnesium sulfate, then, filtrated. The filtrate was concentrated under reduced pressure, then, the residue was subjected to silica gel column chromatography to obtain 0.32 g of (1R)-trans-3-[(E)-3-methoxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylic acid:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](B2OCC(C)(C)CO2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2].C([O:39][C:40]1[CH:45]=[CH:44][C:43](Br)=[C:42]([F:47])[CH:41]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+].O>COCCOC>[C:25]([O:24][CH2:23][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:43]2[CH:44]=[CH:45][C:40]([OH:39])=[CH:41][C:42]=2[F:47])=[CH:13][CH:14]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)NC(CCc1ccc(B2OCC(C)(C)CO2)cc1)(COC(C)=O)COC(C)=O
Reactant: Fc1cc(OCc2ccccc2)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)NC(CCc1ccc(-c2ccc(O)cc2F)cc1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
A mixed solution of N-[1,1-bis(acetoxymethyl)-3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]propyl]acetamide (867 mg) of Reference Example 9, 1-benzyloxy-4-bromo-3-fluorobenzene (674 mg), sodium hydrogen carbonate (1.01 g) and tetrakistriphenylphosphine palladium (46 mg) in 1,2-dimethoxyethane (15 mL)-water (5 mL) was stirred at 65° C. for 5 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To a solution of the residue in methanol (30 mL) were added palladium carbon (10%, 0.3 g) and ammonium formate (517 mg), and the mixture was stirred at room temperature for 6 hr under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.56 g) as white amorphous crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19])[CH:6]=[CH:5]2.C([Li])CCC.[F:25][C:26]1[CH:27]=[C:28]([CH:35]=[CH:36][CH:37]=1)[C:29](N(OC)C)=[O:30]>C1COCC1>[F:25][C:26]1[CH:27]=[C:28]([C:29]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH3:19])[CH:6]=[CH:5]3)=[O:30])[CH:35]=[CH:36][CH:37]=1
Reactant: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Reactant: CON(C)C(=O)c1cccc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1ccc2cc(C(=O)c3cccc(F)c3)ccc2n1
Temperature: 25 °C

Procedure:
The product from Example 42D (320 mg, 1.0 mmol) in THF (10 mL) was treated with 2.5M n-butyllithium (0.5 mL, 1.25 mmol) at −78° C. The solution was mixed for 15 min, and treated with a solution of 3-fluoro-N-methoxy-N-methylbenzamide (2.0 mmol) in THF (5.0 mL) at −78° C. The mixture was allowed to warm to room temperature overnight, quenched by 1 mL ethanol, concentrated, and diluted with ethyl acetate. The mixture was washed with 5% NaHCO3 (25 mL×3), 25% brine (25 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (heptane:acetone:CH2Cl2:TEA (60:40:5:1) to provide the title compound. The title compound was treated with HCl in IPA:ethyl acetate to give the dihydrochloride salt. mp 162-164° C.(dec.); MS (ESI) 363 (M+H)+; 1H NMR (DMSO-d6) δ 8.79 (1H, d), 8.53 (1H, d), 8.30 (1H, d), 8.21(1H, dd), 7.82 (1H, d), 7.6 (4H, m), 3.9 (1H, br, m), 3.63 (2H, br, m), 3.50 (2H, br, m), 3.21 (1H, br, m), 2.2 (1H, m), 1.98 (2H, br, m), 1.7 (1H, br, m), 1.46 (1H, m), 1.30 (3H, d).
Reaction SMILES: COC1C=CC(C2C=NN(COCC[Si](C)(C)C)C=2C)=CC=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([CH3:44])=[N:33][N:34]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=2)=[CH:27][CH:26]=1.[Li]CCCC.C([O:53][B:54](OC(C)C)[O:55]C(C)C)(C)C>C1COCC1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([CH3:44])=[N:33][N:34]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[C:35]=2[B:54]([OH:55])[OH:53])=[CH:27][CH:26]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(-c2cn(COCC[Si](C)(C)C)nc2C)cc1
Agent: COc1ccc(-c2cnn(COCC[Si](C)(C)C)c2C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C)nn(COCC[Si](C)(C)C)c2B(O)O)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-(4-methoxy-phenyl)-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole and 4-(4-methoxy-phenyl)-3-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole (1 eq) was taken up in THF and cooled under nitrogen to −78° C. nBuLi (1.2 eq) was added dropwise and all was stirred for 30 minutes. Triisopropylborate (2.5 eq) was added and the reaction was stirred to room temperature. After 45 minutes, the reaction mixture was quenched with water and extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a gum. This was purified by flash chromatography (9:1 hexane: EtOAc) to give 4-(4-methoxy-phenyl)-3-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole-5-boronic acid as an oil.