Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:40]=[CH:39][C:19]2[N:20]([CH3:38])[C:21]([NH:23][C:24]3[S:25][C:26]4[CH:32]=[C:31]([O:33][C:34]([F:37])([F:36])[F:35])[CH:30]=[CH:29][C:27]=4[N:28]=3)=[N:22][C:18]=2[CH:17]=1)=[O:15])(C)(C)C.[ClH:43]>>[ClH:43].[ClH:43].[CH3:6][NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:40]=[CH:39][C:19]2[N:20]([CH3:38])[C:21]([NH:23][C:24]3[S:25][C:26]4[CH:32]=[C:31]([O:33][C:34]([F:37])([F:35])[F:36])[CH:30]=[CH:29][C:27]=4[N:28]=3)=[N:22][C:18]=2[CH:17]=1)=[O:15]
Reactant: CN(CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C)C(=O)OC(C)(C)C
Agent: Cl
Product: CNCCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-methylamino-ethoxy)-ethyl]-amide dihydrochloride (53 mg) was prepared by following General Procedure L using methyl-[2-(2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethoxy)-ethyl]-carbamic acid tert-butyl ester (60 mg) and hydrogen chloride (250 uL, 4.0 M solution in 1,4-dioxane). LC/MS: m/z 509.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[N:14]2)([CH2:11][CH3:12])[CH:9]=[O:10])=[CH:4][CH:3]=1.[CH3:30][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[N:14]2)([CH2:11][CH3:12])[CH:9]([OH:10])[CH3:30])=[CH:4][CH:3]=1
Reactant: CCC(C=O)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(c1ccc(Cl)cc1)(C(C)O)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 1-[2-(4-chlorophenyl)-1-oxobutan-2-yl]-1H-indazol-4-ylcarbamate (2.50 g, 6.05 mmol) in anhydrous THF (50 mL) was added methylmagnesium bromide (2.5 M in ether, 7.3 mL, 18.15 mmol) at 0° C. The mixture was stirred for anther 30 min at 0° C., then saturated NH4Cl (100 mL) was added and the mixture was extracted with EA. The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to provide the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.[CH2:20]([O:27][C:28](=[O:41])[CH2:29][CH2:30][NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28](=[O:41])[CH2:29][CH2:30][NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH:34]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CC(=O)Nc2cccc(C(=O)NCCC(=O)OCc3ccccc3)c2)cc1

Procedure:
p-Cyanophenylacetic acid and N-(m-aminobenzoyl)-β-alanine benzyl ester trifluoroacetate are coupled to give N-[m-[2-(p-cyanophenyl)acetamido]benzoyl]-β-alanine benzyl ester, m.p. 98°-99° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[C@H:4]1[O:51][C@@H:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][N:44]5[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]5)=[CH:37][CH:36]=4)[C:18]4[C:23]([C:24]=3[CH3:25])=[CH:22][C:21]([O:26]CC3C=CC=CC=3)=[CH:20][CH:19]=4)=[CH:12][CH:11]=2)[C@:7]([C:53](=[O:55])[CH3:54])([OH:52])[C@@:6]([C:57](=[O:59])[CH3:58])([OH:56])[C@@H:5]1[O:60][C:61](=[O:63])[CH3:62]>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:64])[C@H:4]1[O:51][C@@H:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][N:44]5[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]5)=[CH:39][CH:40]=4)[C:18]4[C:23]([C:24]=3[CH3:25])=[CH:22][C:21]([OH:26])=[CH:20][CH:19]=4)=[CH:12][CH:11]=2)[C@:7]([C:53](=[O:55])[CH3:54])([OH:52])[C@@:6]([C:57](=[O:59])[CH3:58])([OH:56])[C@@H:5]1[O:60][C:61](=[O:63])[CH3:62]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc(-c3c(C)c4cc(OCc5ccccc5)ccc4n3Cc3ccc(OCCN4CCCCCC4)cc3)cc2)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc(-c3c(C)c4cc(O)ccc4n3Cc3ccc(OCCN4CCCCCC4)cc3)cc2)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@@H]1OC(C)=O

Procedure:
Glycosidated indole 34 (3.7 g, 4.2 mmol) in 60 mL THF/MeOH (1:1) was treated with 10% Pd/C (1.5 g) and hydrogenated in a Parr apparatus at 40 psi for 23 h. The reaction mixture was filtered through a bed of Celite and the filter cake was washed with THF (20 mL) and EtOH (20 mL). To avoid any air oxidation, L-ascorbic acid (0.37 g) was added to the filtered solution. The solution was concentrated and chromatographed on silica gel using CHCl3/i-PrOH (7:1) to render the product 35 (1.6 g, 48%) as a brown foam: Rƒ=0.20 (7:1 CHCl3:iPrOH); 1H NMR (DMSO) 6.5-7.5 (m, 11H), 5.7 (d, 1H, J=7.9 Hz), 5.5 (t, 1H, J=9.6 Hz), 4.9-5.2 (m, 4H), 4.7 (d, 1H, J=9.9 Hz), 3.6 (s, 3H), 3.3 (s, 8H), 2.1 (s, 3H), 1.9-2.2 (m, 9H), 1.5-1.9 (m, 8H); 3C NMR (CDCl3) 170.0, 169.0, 167.0, 157.0, 156.5, 150.0, 138.0, 131.7, 131.6, 130.0, 127.3, 116.9, 114.7, 112.0, 111.0, 108.0, 104.5, 98.8, 72.6, 71.8, 71.1, 69.1, 64.4, 55.0, 55.2, 53.0, 47.0, 26.7, 23.6, 20.6, 20.5, 9.5; IR (KBr): υmax 3427, 3037, 2935, 2612, 1757, 1612, 1510, 1462, 1374, 1227, 1040 cm−1; LC/MS (ESI) retention time=13.0, M+H+=787.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:16][NH:17][CH3:18]>CN(C=O)C.C(OCC)(=O)C>[CH3:16][N:17]([CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13])[CH3:18]
Reactant: CNC
Reactant: COC(=O)c1oc2ccccc2c1CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1oc2ccccc2c1CN(C)C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
To a solution of methyl 3-bromomethylbenzofuran-2-carboxylate (269 mg, 1.0 mmol) in DMF was added dimethylamine (2M solution in THF, 1.5 ml, 3 mmol). The reaction mixture was stirred for 1-2 h, diluted with ethyl acetate (50 ml), washed twice with saturated aqueous sodium bicarbonate solution (50 ml) and finally with brine (50 ml). The organic extract was dried over sodium sulfate and then concentrated in vacuo. Purification by flash chromatography on silica gel (5% methanol in dichloromethane) gave methyl 3-dimethylaminomethylbenzofuran-2-carboxylate (131 mg, 0.57 mmol).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][NH2:20])[CH2:14]1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:27]>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][NH:20][C:26](=[O:27])[O:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)[CH2:14]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Yield: 49.6 %

Procedure:
Triethylamine (0.09 ml) was added to solution of Intermediate 3 (0.150 g, 0.545 mmol) in dichloromethane (3 ml) with stirring at 20° C. under nitrogen. The solution was cooled to 0° C. and a solution of 4-nitrophenyl chloroformate (0.121 g) in dichloromethane (1 ml) was added drop-wise. The resultant mixture was stirred for 4 h at 0° C. The solution was allowed to warm to 20° C., washed with brine (4 ml), dried (MgSO4), and concentrated in vacuo. Purification by Biotage flash chromatography on silica gel, eluting with 35% ethyl acetate in cyclohexane, gave the title compound as a pale yellow solid (0.119 g). LC/MS (system A) Rt 3.01 min, Mass Spectrum m/z 441 [MH+].
Reaction SMILES: S(=O)(=O)(O)O.N[C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][CH:9]([CH3:11])[CH3:10].[K+].[Br-:16].N([O-])=O.[Na+]>C1(C)C=CC=CC=1.O>[Br:16][C@H:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:12]([OH:14])=[O:13]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: [Br-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](Br)C(=O)O
Temperature: -10 °C

Procedure:
Concentrated sulfuric acid (16.16 g, 0.16 mol) was slowly added to 110 g of water and, successively, L-leucin (8.68 g, 0.066 mol), KBr (39.4 g, 0.33 mol) and 50 ml of toluene were added successively. The slurry was cooled to −10° C. and sodium nitrite dissolved in 12.9 g of water (7.0 g, 0.10 mol) was added for 2 hours. After stirring at −10° C. over one night, temperature was elevated to a room temperature and the liquid was separated. The aqueous layer was discarded and the obtained organic layer was washed twice each with 30 ml of water to obtain a toluene solution of (R)-2-bromo-4-methyl valeric acid. When the optical purity of the (R)-2-bromo-4-methyl valeric acid was evaluated by HPLC, it was 98.0% ee.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:39]=[CH:38][CH:37]=[CH:36][C:5]=1[C:6]([NH:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([N:20]3[CH2:24][CH2:23][C:22]4([CH2:29][CH2:28][N:27](C(=O)C(F)(F)F)[CH2:26][CH2:25]4)[CH2:21]3)=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7]>CO>[CH2:21]1[C:22]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:24][N:20]1[C:18]([C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH:9]2[NH:8][C:6](=[O:7])[C:5]2[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=2[Cl:3])=[CH:13][CH:14]=1)=[O:19]
Reactant: O=C(NC1CCc2ccc(C(=O)N3CCC4(CCN(C(=O)C(F)(F)F)CC4)C3)cc21)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC1CCc2ccc(C(=O)N3CCC4(CCNCC4)C3)cc21)c1ccccc1Cl
Reaction time: 5 h

Procedure:
2 M KOH solution (4 ml) was added to a stirred solution of 2-chloro-N-(6-(8-(2,2,2-trifluoroacetyl)-2,8-diazaspiro[4.5]decane-2-carbonyl)-2,3-dihydro-1H-inden-1-yl)benzamide (200 mg, 0.374 mmol, 1 eq.) in MeOH (4 ml) and the mixture was stirred for 5 h. Methanol was removed under reduced pressure and it was diluted with EtOAc (100 ml) and washed with water (10 ml) and brine (20 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to dryness. The crude material was used for the next step without further purification.
Reaction SMILES: CS(C1C=C[C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].N1CCCCC1>>[CH3:31][NH:30][S:29]([C:26]1[CH:27]=[CH:28][C:20]([N:14]2[CH2:8][CH2:15][CH2:16][CH2:17][CH2:18]2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])(=[O:33])=[O:32]
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc(N2CCCCC2)c(C(=O)O)c1
Yield: 48 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example S) from 2-Chloro-5-methylsulfamoyl-benzoic acid and piperidine and obtained in 48% yield. MS (m/e): 297.4 MH− (100%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[CH:18]2)=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li][CH2:29][CH2:30]CC.CCCCCC.C(I)C>O1CCCC1.O>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[C:18]2[CH2:29][CH3:30])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(-n2cnc(-c3ccccc3)c2)cc1
Reactant: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred solution of 1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-4-phenyl-1H-imidazole (1.89 g, 5.0 mmol) in tetrahydrofuran (40 mL) was added a solution of 1.5 M n-BuLi in hexane (3.5 mL, 5.5 mmol) at −78° C. over 10 min. After 30 min, a solution of ethyl iodide (2.0 mL, 25.0 mmol) in tetrahydrofuran (10 mL) was added slowly to the mixture at −78° C. The resultant mixture was warmed to room temperature and stirred for 2 h. To the reaction mixture was added water and the volatile components were removed under reduced pressure. The aqueous phase was extracted with ethyl acetate and the combined organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 10:1 to 6:1) to afford 1.86 g (92%) of the title compound as pale yellow oil: MS (ESI) m/z 379 [M+H]+1H-NMR (CDCl3)δ0.00 (6H, s), 0.88 (9H, s), 1.26 (3H, t, J=7.5 Hz), 2.73 (2H, q, J=7.5 Hz), 2.91 (2H, t, J=6.6 Hz), 3.89 (2H, t, J=6.6 Hz), 7.22-7.28 (4H, m), 7.33-7.41 (4H, m), 7.81 (2H, d, J=7.1 Hz).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Cl:6][C:7]1[C:8]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:9]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[NH2:10]>FC(F)(F)C(O)=O>[Cl:6][C:7]1[C:8]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:9]([C:11]([N+:1]([O-:4])=[O:2])=[CH:12][C:13]=1[O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[NH2:10]
Reactant: Nc1ccc(Oc2cccnc2)c(Cl)c1Oc1cccnc1
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1c([N+](=O)[O-])cc(Oc2cccnc2)c(Cl)c1Oc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
315 mg of potassium nitrate was added to a trifluoroacetic acid (20 ml) solution of 891 mg of 3-chloro-2,4-bis(pyridin-3-yloxy)aniline, and the reaction liquid was stirred overnight at room temperature, and then the solvent was evaporated away under reduced pressure. The residue was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified with silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1 to ethyl acetate) to obtain the entitled compound as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]#[N:17])/[C:8]([O:10]CC)=[O:9])[N:6]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+]>CN(C)C=O.O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]2[NH:17][N:20]=[N:19][N:18]=2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCC#N)c1csc(N)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/OCc2nnn[nH]2)C(=O)O)cs1
Reaction time: 1 h
Yield: 73.7 %

Procedure:
5.0 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetate are heated to 60° C. for 48 hours while stirring together with 1.95 g of sodium azide and 1.6 g of ammonium chloride in 50 ml of dimethylformamide. The mixture is taken up in water/ethyl acetate. The ethyl acetate phase is washed twice with a small amount of water. The combined aqueous phases are concentrated to dryness, the residue is dissolved in 50 ml of 1N aqueous sodium hydroxide solution and stored at room temperature for 1 hour. The mixture is subsequently diluted with 50 ml of water and the solution is concentrated to 50 ml. The product crystallizes after the addition of 50 ml of aqueous 1N hydrochloric acid. There are obtained 3.9 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-(1H-tetrazol-5-yl-methoxy)imino]-acetic acid of melting point 151°-152° C. The water content is 6.96%.
Reaction SMILES: [Ni:1].[C:2]1([CH3:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O-:12])(=[O:11])C>>[Ni:1].[CH2:2]([CH:7]([CH2:6][CH2:5][CH2:4][CH3:3])[C:9]([OH:12])=[O:11])[CH3:8]
Reactant: Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: [Ni]
Product: CCCCC(CC)C(=O)O

Procedure:
The concentration of nickel in the acetate solution is practically 1 ppm or more, preferably, 10 ppm or higher. In case of using a nonpolar solvent such as toluene for obtaining a solution of 2-ethyl hexanoic acid nickel, the oxide 13 is unnecessary and the solution can be directly formed on the amorphous silicon Film.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=O)[C:5]([O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].[CH:23]1(B(O)O)[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>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].C1(C)C=CC=CC=1>[CH:23]1([C:2]2[CH:7]=[C:6]([CH2:8][OH:10])[C:5]([O:12][CH2:13][CH3:14])=[CH:4][C:3]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:25][CH2:24]1
Reactant: CCOc1cc(-c2ccc(F)cc2F)c(Br)cc1C(=O)OC
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1cc(-c2ccc(F)cc2F)c(C2CC2)cc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A mixture of methyl 2-bromo-5-ethoxy-2′,4′-difluorobiphenyl-4-carboxylate (22.6 g), cyclopropylboronic acid (13.1 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (3.75 g), a 2 M aqueous sodium carbonate solution (91 mL), tris(dibenzylideneacetone)dipalladium(0) (3.91 g), and toluene (150 mL) was stirred overnight at 100° C. in an argon atmosphere. The reaction mixture was allowed to cool to room temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). A THF (50 mL) solution of the purified product was added to a THF (50 mL) suspension of lithium aluminum hydride (2.5 g) under ice cooling in a nitrogen atmosphere. After stirring at the same temperature as above for 30 minutes, water (2.5 mL) and a 15% aqueous sodium hydroxide solution (2.5 mL) were added thereto, and the mixture was stirred for 5 minutes. Water (7.5 mL) was further added to the reaction mixture, and the mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (16.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]([F:14])([F:13])[F:12])=[CH2:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19](Cl)([CH:20]=[N:21][OH:22])[CH2:18][C:17]=1[CH3:26].C(=O)([O-])O.[K+]>O1CCCC1>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:11]([F:14])([F:12])[F:13])[O:22][N:21]=2)=[CH:18][C:17]=1[CH3:26]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC1=C(Br)C=CC(Cl)(C=NO)C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Yield: 90.5 %

Procedure:
In a solution of 22.7 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene produced in Step 1 of Synthetic Example 3 and 26.0 g of 4-bromo-1-chloro-3-methylbenzaldoxime in 120 ml of tetrahydrofuran, 15.7 g of potassium hydrogen carbonate was added, and stirred under reflux with heat for 5 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off, then the solvent was distilled off under reduced pressure. 150 ml of water was added in the residue, stirred at room temperature for 18 hours, and precipitated crystal was filtered off and dried to obtain 38.6 g of the aimed product as white crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:15]2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[C:22]([NH:21][CH2:20][C:19]([N:16]1[CH2:17][CH2:18][CH:14]([N:11]2[CH2:10][CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:13][CH2:12]2)[CH2:15]1)=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.9 %

Procedure:
To N-(2-(3-(4-(2-aminophenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)-3,4-dichlorobenzamide (Example #4.149, 0.063 g, 0.13 mmol) in DCM (1 mL) was added triethylamine (0.037 mL, 0.26 mmol) and methanesulfonyl chloride (0.011 mL, 0.14 mmol). The reaction mixture was stirred at room temperature for about 16 h. The solvent was removed in vacuo and the residue was purified by RP-HPLC (10% acetonitrile/0.05M aqueous ammonium acetate, buffered to pH 4.5 for 3 min., 5% to 60% acetonitrile/0.05M aqueous ammonium acetate over 6 min at 22.5 mL/min with 2.5 mL/min. acetonitrile at-column dilution; APCI positive mode detection; Xterra prep. MS C18. 19×50 mm column) to afford 3,4-dichloro-N-(2-(3-(4-(2-(methylsulfonamido)phenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)benzamide (0.0052 g, 0.009 mmol). RP-HPLC (Table 1, Method a) Rt 2.07 min; m/z: (M+H)+ 553.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[C:16]([C:20]1[S:21][C:22]2[C:27](=[O:28])[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31](B4OC(C)(C)C(C)(C)O4)[C:30]=3[CH3:44])[CH2:25][C:23]=2[N:24]=1)([CH3:19])([CH3:18])[CH3:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>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].O1CCOCC1>[C:16]([C:20]1[S:21][C:22]2[C:27](=[O:28])[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:2]4[CH:3]=[C:4]([NH:9][C:10]5[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=5)[C:5](=[O:8])[NH:6][N:7]=4)[C:30]=3[CH3:44])[CH2:25][C:23]=2[N:24]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Reactant: Cn1ccc(Nc2cc(Cl)n[nH]c2=O)n1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2cc(Nc3ccn(C)n3)c(=O)[nH]n2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Temperature: 110 °C
Yield: 30.7 %

Procedure:
A 5 mL pressure tube was charged with 6-chloro-4-(1-methyl-1H-pyrazol-3-ylamino)pyridazin-3(2H)-one 109g (20.0 mg, 0.089 mmol), 2-tert-butyl-5-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 109f (43.9 mg mg, 0.11 mmol), 1.27 M of potassium phosphate in water (0.15 mL, 0.20 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.1 mg, 0.0044 mmol), S-Phos (4.4 mg, 0.011 mmol), and 1,4-dioxane (1.4 mL). The mixture was purged with nitrogen, sealed, and heated at 110° C. overnight. The reaction mixture was cooled to room temperature, and filtered through Celite®. The filter cake was washed with methylene chloride/methanol (˜9:1). The filtrate was concentrated. The residue was purified on silica eluted with a gradient of 0 to 3.5% methanol in methylene chloride. The material obtained was further purified by reverse phase HPLC: C-18 column, eluted with a gradient of 0 to 80% acetonitrile in water over 20 min with 0.05% trifluoroacetic acid to afford 2-tert-butyl-5-(2-methyl-3-(5-(1-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one (109) (13 mg, 31%). M+1476.2. 1H NMR (400 MHz, DMSO) δ 12.92 (s, 1H), 9.17 (s, 1H), 7.72 (s, 1H), 7.48 (d, J=2.2, 1H), 7.44 (dd, J=5.3, 3.9, 1H), 7.32 (dd, J=6.5, 2.7, 2H), 6.08 (d, J=2.3, 1H), 4.91 (s, 2H), 3.67 (s, 3H), 2.07 (s, 3H).