Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([SH:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:14])[CH3:2].[OH:15][C@:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13][C:27]3[CH:28]=[C:23]([C@@:16]4([OH:15])[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]4)[CH:24]=[CH:25][CH:26]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:14])[CH3:2]
Reactant: CCN1C(=O)CCc2cc(S)ccc21
Reactant: C[C@H]1C[C@@](O)(c2cccc(I)c2)CCO1
Product: CCN1C(=O)CCc2cc(Sc3cccc([C@@]4(O)CCO[C@@H](C)C4)c3)ccc21
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 6, 1-ethyl-6-mercapto-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-hydroxy-4-(3-iodophenyl)-2-methyltetrahydropyran to give (2S,4R)-4-[3-(1-ethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-4-hydroxy-2-methyltetrahydropyran in 55% yield, m.p. 148°-149° C. (recrystallised from diethyl ether);
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[N:10]=[C:11]([C:30]#[CH:31])[C:12]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13][CH:14]=1.[OH:32][N:33]=[C:34](Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[Br:8][C:9]1[N:10]=[C:11]([C:30]2[O:32][N:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:31]=2)[C:12]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[N:13][CH:14]=1
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: ON=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Triethylamine (50.82 mg, 70.00 μL, 0.5022 mmol) was added to a solution of tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (200 mg, 0.5022 mmol) and N-hydroxybenzimidoyl chloride (78.13 mg, 0.5022 mmol) in THF (16.00 mL) and the reaction mixture stirred at RT for 1 hour. After this time the reaction mixture was heated under reflux for 3 hours, cooled to RT and concentrated in vacuo. The residue was purified by column chromatography eluting with 10% EtOAc/Petroleum ether to give the product as a colourless oil that crystallised on standing (182 mg, 70% Yield). 1H NMR (400.0 MHz, DMSO) d 1.41 (18H, s), 7.37 (1H, s), 7.52 (3H, m), 7.90 (2H, m), 8.68 (1H, s); MS (ES+) 519.05
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:21][C:20]=1[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=3)=[CH:21][C:20]=2[CH3:35])=[CH:12][CH:13]=1
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
To a solution of 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (0.11 g, 0.49 mmol) and 4-chloromethyl-3-methyl-4′-trifluoromethyl-biphenyl (0.12 g, 0.41 mmol) in acetonitrile (4 mL) is added Cs2CO3 (0.20 g, 0.61 mmol). The mixture is stirred at RT for 12 h. The mixture is diluted with water and extracted with EtOAc. The organics are dried with MgSO4, and the crude material is purified by flash chromatography to yield 0.11 g (58%) of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([OH:12])=[CH:5]2.[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15]>C1COCC1.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>[OH:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:22])=[CH:11][CH:10]=2
Reactant: Oc1cnc2ccc(I)cc2c1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc2ncc(O)cc2c1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A stirred solution of 6-iodoquinolin-3-ol (1.76 g, 6 mmol) in THF (10 mL) was treated with 2-tert-butoxy-2-oxoethylzinc chloride (39 ml, 19 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.8 g, 0.6 mmol). After the addition, it was heated to reflux (75° C.) under N2. After 3 h, TLC 89368-3-1 showed no sign of starting material. Reaction was stop. The reaction was cooled to rt. Solvent was removed. The residue was stirred in EtOAc/10% EDTA (50 mL/50 mL) solution mixture. After 1 h, the organic layer was separated. The aqueous layer was extracted with more EtOAc (2×25 mL). The combined organic layers were washed with water, brine, dried over MgSO4, and removed solvent. The crude product was purified using SiO2 chromatography (TELEDYNE ISCO REDISEP®, PIN 68-2203-026, 12 g sio2, hex:acetone=80%:20%, Flow=30 mL/min). to afford the desired product as brownish liquid. MS m/z: 260.3 (M+H). Calc'd. for C15H17NO3−259.2.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>C(O)(=O)C>[ClH:1].[ClH:1].[CH3:9][C:8]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: Cc1[nH]cnc1CO
Reactant: NCCS
Agent: Cl
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CSCCN
Yield: 184.6 %

Procedure:
A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30 g) and cysteamine hydrochloride (23 g) in acetic acid (200 ml) was heated under reflux for 10 hours. Following cooling to 15°-20° C., the solid which crystallised was collected and washed with isopropyl alcohol to give 2[(5-methylimidazol-4-yl)methyl]thioethylamine dihydrochloride (45.5 g), m.p. 189°-192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[NH2:10])=[CH:5][CH:4]=1.[OH:19][CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:10][C:20]([C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23][CH2:22]2)=[O:19])=[CH:12][CH:13]=1
Reactant: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Reactant: O=C(O)[C@H]1CC[C@H](CO)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC(=O)[C@H]2CC[C@H](CO)CC2)c2ccc(OC)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of bis(4-methoxyphenyl)methanamine (846 mg), trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (500 mg), and triethylamine (1.322 mL) in N,N-dimethylformamide (30 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate reagent (1.677 g). The resulting mixture was stirred for 3 hours, diluted with ethyl acetate, washed with water, aqueous NaOH and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was dissolved in dichloromethane and loaded into a silica cartridge, eluted with 0-100% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Cl:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](OC)=[O:29])=[CH:26][CH:25]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CCCCCC.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([S:14]([CH2:17][C:28](=[O:29])[C:27]2[CH:32]=[CH:33][C:24]([Cl:23])=[CH:25][CH:26]=2)(=[O:15])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CC(=O)c2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-methanesulfonylpiperazine (1.32 g) in tetrahydrofurane (10 ml) was added dropwise at 0° C. 1.6 M n-butyllithium in hexane (6.25 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to −78° C., and to the mixture was added a solution of methyl 4-chlorobenzoate (853 mg) in tetrahydrofurane (5 ml). The mixture was stirred for 3 hours at the same temperature and raised to 0° C. To the reaction solution was added water (10 ml), and the mixture was made acidic with citric acid aqueous solution and extracted with ether. The organic layer was washed with brine, dried, concentrated, and purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give a colorless solid of the title compound (790 mg).
Reaction SMILES: [F:1][C:2]([F:33])([C:18]1[N:22]2[CH:23]=[C:24]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:25]=[CH:26][C:21]2=[N:20][N:19]=1)[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH:12]C(C3CC3)=O)[N:11]=2)[N:8]=1.CO.O>Cl>[F:33][C:2]([F:1])([C:18]1[N:22]2[CH:23]=[C:24]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:25]=[CH:26][C:21]2=[N:20][N:19]=1)[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH2:12])[N:11]=2)[N:8]=1
Reactant: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5nc(NC(=O)C6CC6)cn5n4)n3c2)cn1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5nc(N)cn5n4)n3c2)cn1
Yield: 35.4 %

Procedure:
A solution of 45 (100 mg) in 3N HCl:50% MeOH:water was heated at 50° C. for 3 hrs. The reaction was concentrated and purified by preparative LCMS to provide the title compound, 6-(difluoro(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-amine (30 mg) as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.89 (s, 3 H) 7.46 (br. s., 1 H) 7.51-7.58 (m, 1 H) 7.90 (dd, J=9.47, 1.39 Hz, 1 H) 7.93-7.99 (m, 1 H) 8.04 (d, J=9.60 Hz, 1 H) 8.08 (s, 1 H) 8.39-8.43 (m, 2 H) 8.67 (s, 1 H). ESI-MS:m/z 382.2 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]1[CH:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8]1)=[CH2:2].C[N+]1([O-])CC[O:26]CC1.CC(O)(C)C.[OH2:35]>CC(C)=O.O.O=[Os](=O)(=O)=O>[OH:35][CH:1]([CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]1[CH:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8]1)[CH2:2][OH:26]
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC(CCCC1NC(=O)CC1C)NC(=O)OC(C)(C)C
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: CC1CC(=O)NC1CCCC(NC(=O)OC(C)(C)C)C(O)CO
Reaction time: 18 h

Procedure:
To a stirring solution of the compound from EXAMPLE 259 (3.3 mmol) in 80 mL of acetone:H2O (3:1) is added N-methylmorpholine N-oxide (0.64 g, 4.8 mmol) and 2.5% OsO4 in t-BuOH (3.4 mL, 3.4 mmol). After 18 h, 120 mL of H2O, 8 g of celite, and 1.6 g Na2S2O1 is added to the reaction. The reaction is filtered through a pad of wet celite. To the filtrate is added 200 mL of 1M KHSO4. The filtrate is extracted with 3×200 mL EtOAc. The combined organic layers are dried, filtered, and stripped. The residue is purified by chromatography to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([NH2:16])=[N:14][CH:15]=1)=[O:8].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25].CCN(CC)CC>C(Cl)Cl>[NH2:16][C:13]1[N:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([NH:1][C:24]([C:23]3[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=3)=[O:25])[CH:3]=[CH:4][C:5]=2[CH3:18])=[CH:15][N:14]=1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cnc(N)nc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)Nc1cnc(N)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide 9 (86 mg, 0.353 mmol) was taken up in CH2Cl2(3 mL) and 3-(trifluoromethyl)benzoyl chloride (0.052 mL, 0.353 mmol) was added. The mixture was allowed to stir at rt for 2 h, becoming a thick yellow suspension. NEt3 (0.064 mL, 0.459 mmol) was added. After 0.5 h, a thick yellow suspension remained. Complete consumption of the amine starting material was indicated by LCMS. The crude reaction mixture was concentrated and the title compound was purified using automated medium pressure chromatography (Isco—40 g column; eluting with a linear gradient from 100% CH2Cl2 (A line) to 100% 90/10/1 CH2Cl2/MeOH/NH3 (B line) on silica gel) to afford N-(2-amino-5-pyrimidinyl)-2-methyl-5-(((3-(trifluoromethyl)phenyl)carbonyl)amino)benzamide 10 as an off-white solid. MS: m/z found 416 [MH+] (by ESI, positive ion); MS calculated for C20H16F3N5O2=415.13.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[CH:24]=1>>[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]=1[C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:28])[CH:24]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)NC2CCOCC2)cn1
Yield: 37 %

Procedure:
As described for Example 71, tetrahydro-pyran-4-ylamine was converted, using 2-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (47 mg, 37%) which was obtained as an off-white solid. MS: m/e=429.1 [M+H]+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:14]=[C:15]2[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:32](S(C)(=O)=O)=[N:31][C:16]2=[N:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[NH2:46][C@H:47]1[CH2:51][O:50][C@@H:49]2[C@H:52]([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:53][O:54][C@H:48]12>CN(C=O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]2[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:32]([NH:46][C@H:47]3[CH2:51][O:50][C@@H:49]4[C@H:52]([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:60])([CH3:59])[CH3:61])[CH2:53][O:54][C@H:48]34)=[N:31][C:16]2=[N:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2N
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2Nc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Reaction time: 18 h

Procedure:
DBU (18.3 uL, 0.122 mmol) was added to a mixture of 2-[[6-chloro-2-methylsulfonyl-5-(4-phenylphenyl)imidazo[4,5-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (50 mg, 0.097 mmol) and tert-butyl N-[(3S,3aR,6R,6aR)-3-amino-2,3,3a,5,6,6a-hexahydrofuro-[3,2-b]furan-6-yl]carbamate (72.6 mg, 0.297 mmol) in DMF (0.39 mL). After 18 hours, the mixture was diluted with ethyl acetate (20 mL) and washed with water (5×20 mL). The organic layer was separate, washed with brine (1×10 mL), dried with MgSO4, filtered and the solvent was removed under vacuum. The crude reaction mixture was then purified on preparative silica gel plates (1×1000 u—developed with 30% EtOAc/hexanes and eluted with EtOAc) to give the title compound. LC-MS: calculated for C35H44ClN5O5Si 677.28 observed m/e minor isomer 678.31 (M+H)+ (Rt 1.34/2 min) and major isomer 608.23 (M+H)+ (Rt 1.04/2 min)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=1[CH:5](Cl)Cl.CC1C([N+]([O-])=O)=CC(Cl)=CC=1C(F)(F)F.CC1C(N)=CC=CC=1C(F)(F)F>>[CH3:5][C:4]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:3]=1[C:2]([F:13])([F:1])[F:14]
Reactant: FC(F)(F)c1cc(Cl)ccc1C(Cl)Cl
Agent: Cc1c(N)cccc1C(F)(F)F
Agent: Cc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Product: Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
2-Trifluoromethyl-4-chloro-benzalchloride and 2-methyl-3-nitro-5-chlorobenzotrifluoride, are intermediates in a process of preparing 2-methyl-3-aminobenzo-trifluoride. In this process, 2-trifluoromethyl-4-chlorobenzal-chloride is prepared by chlorinating o-trifluoromethylbenzalhalide, and 2-methyl-3-nitro-5-chlorobenzotrifluoride is prepared at first by hydrogenating the 2-trifluoro-methyl-4-chlorobenzalhalide to form a 2-methyl-5-monochlorobenzotrifluoride and then by nitrating the 2-methyl-5-monochlorobenzotrifluoride. Following this process, 2-methyl-3-aminobenzotrifluoride (MA-BTF) is prepared by hydrogenating the 2-methyl-3-nitro-5-chlorobenzotrifluoride. The thus prepared 2-methyl-3-aminobenzotrifluoride is useful as an intermediate in preparing medicines, agricultural chemicals and other chemical products.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(F)c2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cccc(C2=CCC3(CC2)OCCO3)c1
Temperature: 30 °C
Yield: 100.6 %

Procedure:
The compound (16) (74.6 g), p-toluenesulfonic acid (2.24 g) and toluene (350 ml) were mixed, and the mixture was heated under reflux for 3 hours while water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (500 ml) and toluene (150 ml) were added and mixed to it. The mixture was then allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Then, the solvent of the solution was distilled off under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=7:3 by volume) as an eluent and silica gel as a stationary phase powder and dried, giving 69.7 g of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (17). The yield based on the compound (14) was 86.8%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]#[N:28])=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12.C[Sn]([N:33]=[N+:34]=[N-:35])(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]5[NH:35][N:34]=[N:33][N:28]=5)=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2cccnc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2cccnc2-c2nnn[nH]2)cc1
Temperature: 25 °C

Procedure:
A solution of 7-methyl-2-propyl-3-[[4-(2-cyanopyridin-3-yl)phenyl]methyl]imidazo[4,5-b]pyridine (300 mg, 0.817 mmol) and trimethylstannylazide (504mg, 2.45 mmol) in toluene (3 mL) was heated to reflux for 36 h. The mixture was cooled to rt, concentrated, then purified by flash chromatography on SiO2 (80/20/1 CH2Cl2 /MeOH/NH4OH) to give 7-methyl-2-propyl-3-[[4-[2-(1H-tetrazol-5-yl)-3-pyridinyl]phenyl]methyl]imidazo [4,5-b]pyridine as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=2)[C:9](=[O:20])[N:8]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:7]=1[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=2)[C:9](=[O:20])[N:8]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:7]=1[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C(=O)OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a solution of methyl 4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate (2.98 g, 6.5 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) was added 1N sodium hydroxide (10 mL). The obtained mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (2.62 g, 90.7%) as crystals.
Reaction SMILES: Br[C:2]1[C:3]([C:8](O)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[C:14]([CH3:28])=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:16]=[CH:17][CH:18]=1>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[CH2:8][C@H:3]3[C@@H:2]([C:15]=2[C:14]=1[CH3:28])[CH2:7][CH2:6][CH2:5][NH:4]3
Reactant: O=C(O)c1ncccc1Br
Reactant: COc1cccc(B2OC(C)(C)C(C)(C)O2)c1C
Product: COc1ccc2c(c1C)[C@H]1CCCN[C@H]1C2

Procedure:
The title compound is prepared from 3-bromo-pyridine-2-carboxylic acid and 2-(3-methoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (may be prepared as in WO 2001053268 described) following the synthetic sequence and protocols described for Intermediate 41; since 3-bromo-pyridine-2-carboxylic acid instead of 3-bromo-pyridine-2-carbonitrile is used for the Suzuki-Miyaura coupling (Step 1 of Intermediate 41), hydrolysis of the nitrile (Step 2 of Intermediate 41) is omitted.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([NH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=2[O:37][C:38]([F:41])([F:40])[F:39])(=[O:29])=[O:28])[CH2:21][CH2:20]1)[NH:9]C(OC(C)(C)C)=O)(C)(C)C.C(Cl)[Cl:44]>C(O)(C(F)(F)F)=O>[ClH:44].[ClH:44].[Br:36][C:33]1[CH:34]=[CH:35][C:30]([S:27]([NH:26][CH2:25][C@H:22]2[CH2:23][CH2:24][C@H:19]([CH2:18][NH:17][C:8]([NH2:9])=[NH:7])[CH2:20][CH2:21]2)(=[O:29])=[O:28])=[C:31]([O:37][C:38]([F:40])([F:39])[F:41])[CH:32]=1
Reactant: CC(C)(C)OC(=O)NC(NC[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1)NC(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N=C(N)NC[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1

Procedure:
A solution of trans-[({4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexylmethyl}-amino)-tert-butoxycarbonylamino-methyl]-carbamic acid tert-butyl ester (53 mg, 0.077 mmol) in 50% TFA in CH2Cl2 (2 mL) was stirred at ambient temperature for 3 hr and the reaction mixture was concentrated. To the residue was added a solution of 1 M HCl in Et2O (0.5 mL) and the mixture was concentrated to give trans-4-Bromo-N-(4-guanidinomethyl-cyclohexylmethyl)-2-trifluoromethoxy-benzenesulfonamide dihydrochloride as a white solid (29 mg, 68%).