Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[Br:14][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1ccc(O)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 0.11 mol) in 200 ml of CCl4, was slowly added bromine (18.8 g, 0.11 mol) dissolved in 10 ml of CCl4 at 0° C. for 30 min. The reaction mass was stirred for another 30 min at 0° C. After completion of the reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with water, and 10% sodium bi-sulfite solution, dried over Na2SO4, filtered and concentrated in vacuo to give ethyl 2-(3-bromo-4-hydroxyphenyl)acetate in 78% yield. (22.4 g). 1HNMR (CDCl3): 7.42 (s, 1H); 7.14 (d, 1H); 6.97 (d, 1H); 5.53 (bs, 1H); 4.13 (q, 2H); 3.52 (s, 2H); 1.16 (t, 3H).
Reaction SMILES: N1(CCC(O)=O)C=CN=C1.[CH3:11][N:12]([CH3:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=O)[CH2:18][CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.B.[N:28]1[C:36]2[C:31]3[C:32](=[CH:37][CH:38]=[CH:39][C:30]=3[C:29]=1S)[CH:33]=[CH:34][CH:35]=2>O1CCCC1.C(O)C>[CH3:11][N:12]([CH3:26])[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[C:29]1[C:30]2[CH:39]=[CH:38][CH:37]=[C:32]3[C:31]=2[C:36](=[CH:35][CH:34]=[CH:33]3)[N:28]=1
Reactant: CN(C)CCCNC(=O)CCn1ccnc1
Reactant: SC1=Nc2cccc3cccc1c23
Agent: B
Agent: O=C(O)CCn1ccnc1
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)CCCN(CCCn1ccnc1)C1=Nc2cccc3cccc1c23

Procedure:
3(1H-imidazol-1-yl)propanoic acid is converted to its acid chloride which upon reaction with 3-dimethylaminopropylamine leads to N-(3-dimethylaminopropyl)-3-(1H-imidazol-1-yl)propanamide. Reduction with borane in tetrahydrofuran solution then gives N-(3-dimethylaminopropyl-N-3-(1H-imidazol-1yl))propanamine. Treatment of the latter compound with molar equivalents of benz(cd)indol-2-thiol and mercuric acetate in refluxing ethanol under the conditions of Example 55 then leads to the title compound.
Reaction SMILES: [CH2:1](O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O:13]/[C:14](/[CH3:21])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>P(=O)(O)(O)O.C(O)C>[C:14]([CH:15]([CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:1])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:21]
Reactant: OCC=Cc1ccccc1
Reactant: CCOC(=O)/C=C(/C)OCC
Agent: O=P(O)(O)O
Solvent: CCO
Product: C=CC(c1ccccc1)C(C(C)=O)C(=O)OCC
Temperature: 150 °C
Yield: 85.4 %

Procedure:
The starting material was prepared as follows. To a mixture of 4.02 g of cinnamyl alcohol and 6.6 g of ethyl β-ethoxycrotonate was added 10 mg of phosphoric acid. The resulting mixture was heated to a temperature of 150° C. over a period of about 40 minutes and then heated at 150° C. for 4 hours with stirring while the ethanol formed during the reaction was distilled off. Thereafter, the reaction mixture was distilled to give 6.3 g (81% yield) of ethyl 2-acetyl-3-phenyl-4-pentenoate, boiling point 170°-174° C./20 mmHg.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]O.[H-].[Na+].F[C:10]1[CH:11]=[C:12]([CH:20]([NH:22][CH:23]2[CH2:25][CH2:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.O>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:10]1[CH:11]=[C:12]([CH:20]([NH:22][CH:23]2[CH2:25][CH2:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: CC(NC1CC1)c1cc(F)cc(C(F)(F)F)c1
Reactant: COCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCc1cc(C(C)NC2CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-methoxy-1-propanol (0.14 mL) in N,N-dimethylformamide (3.0 mL) was added 60% oil-based sodium hydride (97 mg), and the mixture was stirred at room temperature for 10 minutes. Then, thereto was added dropwise a solution of N-{1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}cyclopropylamine (300 mg) in N,N-dimethylformamide (1.0 mL), and the mixture was heated to stir at 40° C. for 4 hours. After cooling to room temperature, thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1→2/3) to give N-{1-[3-(3-methoxypropyl)-5-(trifluoromethyl)phenyl]ethyl}cyclopropanamine [REx(31-1)] (227 mg) as a colorless oil.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Si:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([Cl:36])[C:27]=1[NH2:37])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C1COCC1>N1C=CC=CC=1>[Si:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:26]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N:29]=[C:28]([Cl:36])[C:27]=2[N:37]=[C:1]1[OH:2])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OCCCCNc1c(N)c(Cl)nc2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCCCCn1c(O)nc2c(Cl)nc3ccccc3c21
Temperature: 80 °C
Yield: 52.1 %

Procedure:
1,1′-Carbonyldiimidazole (32.6 g, 201 mmol) was added to a solution of N4-[4-(tert-butyldimethylsilanyloxy)butyl]-2-chloroquinoline-3,4-diamine (50.96 g, 134.1 mmol), THF (250 mL), and pyridine (250 mL), and the reaction was heated at 80° C. overnight and allowed to cool. The volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (600 mL), and the resulting solution was washed sequentially with brine (2×400 mL) and water (2×400 mL) and then concentrated under reduced pressure. The resulting solid was triturated with diethyl ether (1 L), collected by filtration, washed with diethyl ether (800 mL), and dried under vacuum for 30 minutes to provide 28.39 g of 1-[4-(tert-butyldimethylsilanyloxy)butyl]-4-chloro-1H-imidazo[4,5-c]quinolin-2-ol as a white solid.
Reaction SMILES: Cl.O.O.Cl[Sn]Cl.[Cl:7][C:8]1[C:33]([N+:34]([O-])=O)=[CH:32][C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[C@@H:15]3[C@H:20]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:19][CH2:18][CH2:17][N:16]3[C:10]=2[CH:9]=1>C(O)C>[NH2:34][C:33]1[C:8]([Cl:7])=[CH:9][C:10]2[N:16]3[CH2:17][CH2:18][CH2:19][C@@H:20]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[C@H:15]3[C:14]3[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=3[O:12][C:11]=2[CH:32]=1
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)c([N+](=O)[O-])cc3Oc3ccccc3[C@H]12)C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc2c(cc1Cl)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Temperature: 60 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
80 μL 36% HCl and SnCl2.2H2O (600 mg, 2.66 mmol) were added trans-N-(7-chloro-8-nitro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (215 mg, 0.49 mmol) in 10 mL of ethanol. The resulting mixture was stirred at 60° C. for 18 h. After cooling the mixture was evaporated and dissolved in ethyl acetate. Aq. sodium bicarbonate was added to the solution (Sn salts were formed) followed by decalite and the mixture was filtered. The filtrate was extracted with ethyl acetate and the organic layer was washed with brine, dried (Na2SO4) and evaporated to give the title compound (194 mg, 82%). Data: (m/z)=413 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH2:10][CH:11]=O)[CH3:9])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1.[NH:40]1[CH2:43][CH:42]([OH:44])[CH2:41]1.CC(O)=O.C([BH3-])#N.[Na+]>C1COCC1.CO.CCOC(C)=O>[Cl:1][C:2]1[C:7]([CH:8]([CH2:10][CH2:11][N:40]2[CH2:43][CH:42]([OH:44])[CH2:41]2)[CH3:9])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C(C)CC=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: OC1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C(C)CCN4CC(O)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
2-((2-chloro-5-cyano-3-(4-oxobutan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (23 mg, 0.043 mmol) was taken up in THF (0.3 mL) and a solution of azetidin-3-ol (6.21 mg, 0.085 mmol) in MeOH (0.200 mL) was added. A drop of AcOH was added and the solution was stirred for 10 min. Next, sodium cyanoborohydride (5.34 mg, 0.085 mmol) was added and the reaction was stirred for 1 h. The reaction was diluted with EtOAc and washed with 2M K3PO4 solution. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-10% MeOH/DCM; 12 g column). 2-((2-chloro-5-cyano-3-(4-(3-hydroxyazetidin-1-yl)butan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (13 mg) was obtained as a yellow glass.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C(OC([N:15]1[CH2:20][CH2:19][C:18]([OH:30])([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:17][CH2:16]1)=O)(C)(C)C>>[ClH:1].[OH:30][C:18]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: Cc1ccccc1OCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1OCC1(O)CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
After adding 5 ml of 4N hydrogen chloride/ethyl acetate to 154 mg of 1-(tert-butoxycarbonyl)-4-hydroxy-4-(2-methylphenoxymethyl)piperidine, the mixture was stirred for 3 hours at room temperature. The solvent was distilled off under reduced pressure to obtain 4-hydroxy-4-(2-methylphenoxymethyl)piperidine hydrochloride (123 mg, 100% yield). The title compound (28 mg, 46% yield) was then obtained in the same manner as Example 1 from 29 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 41 mg of the 4-hydroxy-4-(2-methylphenoxymethyl)piperidine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:8].[H-].[Na+].C1(C)C=C(C)C=C(C)C=1S(O[NH2:31])(=O)=O>CN(C=O)C>[NH2:31][N:4]1[CH:5]=[CH:6][C:2]([CH3:1])=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:8]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Cc1ccccc1NC(=O)c1[nH]ccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)c1c(C)ccn1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
3-Methyl-N-o-tolyl-1H-pyrrole-2-carboxamide (1.5 g, 7.00 mmol) was dissolved in 60 mL of DMF. 294 mg (7.35 mmol) of sodium hydride (60 wt % dispersion in mineral oil) were added and the reaction mixture was stirred at room temperature for 1 hour. Then O-(mesitylsulfonyl)hydroxylamine (1.658 g, 7.70 mmol) was added and the reaction mixture was stirred for 30 minutes. The solvent was evaporated to dryness and the crude product was purified by flash chromatography (0 to 50% heptane/AcOEt) to give 1.17 g (73% yield) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]4[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=4)=[N:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH:4]=[N:3]1.[N:29]([CH2:32][CH3:33])=[C:30]=[O:31]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:20]([C:21]4[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:30]([NH:29][CH2:32][CH3:33])=[O:31])=[CH:27][CH:28]=4)=[N:19][CH:18]=[CH:17][N:16]=3)[CH2:13][CH2:14]2)[CH:4]=[N:3]1
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CN)cc3)CC2)cnn1C
Reactant: CCN=C=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCNC(=O)NCc1ccc(-c2nccnc2N2CCN(Cc3cnn(C)c3C)CC2)cc1
Temperature: 50 °C
Yield: 66.9 %

Procedure:
Dissolve 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamine (0.35 g, 0.93 mmol) in tetrahydrofuran (6 mL). Add isocyanato-ethane (1 eq., 0.06 g, 0.84 mmol). Add 4-(dimethylamino)pyridine (0.05 eq., 0.005 g, 0.043 mmol). Heat at 50° C. for 17 hr. Purify by normal phase chromatography with eluent 4% 7N ammonia-methanol/ethyl acetate to give 1-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzyl}-3-ethyl-urea (0.252 g, 62%). MS (ES): m/z=449.3[M+H]. Dissolve (0.252 g, 0.56 mmol) in acetonitrile (1 mL) and water (4 mL). Add aq. 1 N HCl (1 eq., 0.56 mmol, 0.56 mL). Freeze the solution to −78° C. in a dry-ice/acetone bath. Place the solution in the lyophilizer for 48 hr. to give the title compound (0.250 g, 97% yield). MS (ES): m/z=449.3 [M+H].
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH2:10][CH2:11][CH2:12]2)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6](=[O:18])[C:5]3=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>CS(C)=O>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:13]3=[C:14]4[N:9]([CH2:10][CH2:11][CH2:12]3)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6](=[O:18])[C:5]4=[CH:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cn2c3c(c(Cl)ccc3c1=O)CCC2
Agent: Cl
Solvent: CS(C)=O
Product: CN1CCN(c2ccc3c(=O)c(C(=O)O)cn4c3c2CCC4)CC1
Yield: 20.1 %

Procedure:
4.0 g of 8-chloro-6,7-dihydro-1-oxo-1H,5H-benzo-[ij]quinolizine-2-carboxylic acid and 4.6 g of N-methylpiperazine was added to 10 ml of anhydrous dimethylsulfoxide and the mixture was heated on an oil bath at 150° to 160° C. for 8 hours while stirring. After completion of the reaction, the solvent and excessive methylpiperazine were removed under reduced pressure and a mixture of methanol and diethyl ether was added to form precipitates which were separated by filtration and washed with diethyl ether. The crystals thus obtained were suspended in 20 ml of a 10% aqueous hydrochloric acid solution and insoluble materials were removed by filtration. The filtrate was purified through column chromatography using Amberlite LH-20 (a trade name for a product of Tokyo Organic Chemical Industries Ltd.) (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gave 1.0 g of 8-(4-methyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo-[ij]quinolizine-2-carboxylic acid light yellow plates having a melting point of 278° to 280.5° C.
Reaction SMILES: C[Si](C)(C)[Cl:3].N[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=2)[CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)=[N:17]2)[N:8]=1>ClCCl.N([O-])=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:3][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=2)[CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)=[N:17]2)[N:8]=1
Reactant: Nc1nc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)no1
Reactant: C[Si](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=N[O-]
Solvent: ClCCl
Product: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(-c2noc(Cl)n2)c1

Procedure:
37.2 1.14 ml (9.00 mmol) of trimethylchlorosilane are added to a suspension of 381 mg (1.00 mmol) of 2-[3-(5-amino-1,2,4-oxadiazol-3-yl)-benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one in 5 ml of dichloromethane. A solution of 865 mg (3.00 mmol) of tetrabutylammonium nitrite in 3 ml of dichloromethane is slowly added dropwise to this suspension at room temperature with stirring. After the reaction mixture has been stirred at room temperature for 16 hours, it is filtered. The filtrate is partitioned between dilute sodium hydrogencarbonate solution and dichloromethane. The organic phase is dried over sodium sulfate and evaporated, giving crude 2-[3-(5-chloro-1,2,4-oxadiazol-3-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one as yellowish oil, which is employed for the next reaction without further purification; ESI 401.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:6]2[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][O:1][C:20](=[O:22])[CH3:21])[NH:4][CH:5]=2)=[CH:17][CH:16]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(COc2c[nH]c(CO)cc2=O)cc1
Solvent: c1ccncc1
Product: COc1ccc(COc2c[nH]c(COC(C)=O)cc2=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
2-(Hydroxymethyl)-5-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one (3.21 g, 12.2 mmol) was dissolved in pyridine (60 mL), added acetyl chloride (1.44 g, 18.3 mmol) under ice-cold conditions, and the mixture was stirred at 60° C. overnight. Then, the reaction solution was concentrated in vacuo. Water was added under ice-cold conditions, and stirred at room temperature for 30 minutes. The deposited solid was filtered, washed with iced water and diethyl ether, concentrated in vacuo, and the title compound (3.56 g (yield 96%)) was obtained as brown powder crystal.
Reaction SMILES: C[Mg]Br.[C:4]1(C)C=CC=CC=1.[CH2:11]([O:13][P:14]([N:19]1[CH:25]2[CH:20]1[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:24]2)([O:16][CH2:17][CH3:18])=[O:15])[CH3:12].O>C1COCC1>[CH2:11]([O:13][P:14]([NH:19][C@H:25]1[C@H:20]([CH3:4])[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24]1)([O:16][CH2:17][CH3:18])=[O:15])[CH3:12]
Reactant: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Reactant: Cc1ccccc1
Agent: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a suspension of Cu(I)I (0.10 g, 0.54 mmol) in THF (20 mL) was slowly added 1.40M methylmagnesium bromide (15.5 mL, 21.7 mmol) in 3:1 toluene:THF at −30° C. After stirring at that temperature for 15 minutes, a solution of benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (2.00 g, 5.43 mmol, Example H, Step D) in THF (10 mL) was added at −30° C. The mixture was then slowly warmed to 0° C. in 2 hours and stirred at 0° C. for 2 hours. Water (20 mL) was added and extracted with ethyl acetate (2×30 mL), washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (ethyl acetate) to give trans-benzyl 3-(diethoxyphosphorylamino)-4-methylpiperidine-1-carboxylate (1.00 g, 48%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[CH:15]1([C:13]([NH:12][C:7]2[N:8]=[CH:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([O:1][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=3)=[O:14])[CH2:16][CH2:17]1
Reactant: O=C(Nc1cc2ccc(O)cc2cn1)C1CC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 100 °C
Yield: 80.5 %

Procedure:
A mixture of N-(7-hydroxyisoquinolin-3-yl)cyclopropanecarboxamide (53 mg, 0.23 mmol), ethyl 2-bromoisobutyrate (69 uL, 0.47 mmol), cesium carbonate (166.8 mg, 0.5119 mmol), and 1,4-dioxane (2.0 mL, 26 mmol) was heated in a sealed vial at 100° C. for 22 hours. The reaction mixture was poured into ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo to yield 63.4 mg (80%) of ethyl 2-(3-(cyclopropanecarboxamido)isoquinolin-7-yloxy)-2-methylpropanoate which was carried forward without purification. LCMS (ESI): M+H=343.2.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.CN(C)CCCN=C=NCC.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]3[N:43]=[CH:42][N:41]([C:44]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:40]=3)=[CH:36][CH:37]=2)[C:32]([C:63]2[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=2)=[N:31]1>ClCCl>[O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:69][C:65]1[CH:66]=[CH:67][CH:68]=[C:63]([C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[C:35]([C:39]4[N:43]=[CH:42][N:41]([C:44]([C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[C:57]5[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=5)[N:40]=4)[CH:34]=3)[N:30]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)[N:31]=2)[CH:64]=1)=[O:5]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C(=O)c1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 2-oxo-2-phenylacetic acid (0.074 g, 0.498 mmol) in 2.0 mL of dichloromethane, was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) as a solid (0.098 g, 0.510 mmol). The solution was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol), dissolved in 1 mL of dichloromethane was added. After 2 days at room temperature, the reaction was not complete. Another 2 equivalents of EDCI were added to the mixture, driving the reaction to completion within 12 hours. The reaction mixture was then partitioned between dichloromethane and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 735 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:13]SC)=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1Cl.NC1C(CSC)=C(C(F)(F)F)C=CC=1Br.NC1C(CSC)=C(C(F)(F)F)C=CC=1I.NC1C(CSC)=C(C(F)(F)F)C=CC=1SC.NC1C(SC)=C(C(F)(F)F)C=CC=1SCC.NC1C(CSC)=C(C(F)(F)F)C=CC=1SCCC.NC1C(CSC)=C(C(F)(F)F)C=CC=1SCCCC.NC1C(CSC)=C(C(F)(F)F)C=CC=1SCCCCCCC.NC1C(CSC)=C(C(F)(F)F)C=CC=1SCCCCCCCC>>[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CSCc1c(C(F)(F)F)ccc(Cl)c1N
Agent: CCCCCCCCSc1ccc(C(F)(F)F)c(CSC)c1N
Agent: CCCCCCCSc1ccc(C(F)(F)F)c(CSC)c1N
Agent: CCCCSc1ccc(C(F)(F)F)c(CSC)c1N
Product: Cc1c(N)cccc1C(F)(F)F

Procedure:
Similarly, the 3-amino-4-chloro-2-methylthiomethylbenzotrifluoride may be replaced with equivalent quantities of 3-amino-4-bromo-2-methylthiomethylbenzotrifluoride, 3-amino-4-iodo-2-methylthiomethylbenzotrifluoride, 3-amino-4-methylthio-2-methylthiomethylbenzotrifluoride, 3-amino-4-ethylthio-2-methylthiobenzotrifluoride, 3-amino-4-n-propylthio-2-methylthiomethylbenzotrifluoride, 3-amino-4-n-butylthio-2-methylthiomethylbenzotrifluoride, 3-amino-4-heptylthio-2-methylthiomethylbenzotrifluoride, or 3-amino-4-octylthio-2-methylthiomethylbenzotrifluoride, and by following substantially the process of Example 2, step B, there is produced 3-amino-2-methylbenzotrifluoride.