Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH2:9][NH2:10])=[CH:3][CH:2]=1.[N+:11]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[CH:17][CH2:18]Cl)([O-:13])=[O:12]>C(O)C>[N+:11]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1/[CH:16]=[CH:17]/[CH2:18][NH:10][CH2:9][CH2:8][NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([O-:13])=[O:12]
Reactant: NCCNc1ccncc1
Reactant: O=[N+]([O-])c1ccccc1C=CCCl
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1/C=C/CNCCNc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
A solution of 11 g of N-(4-pyridyl)ethylenediamine and 5.3 g of 2-nitrocinnamyl chloride (trans-form) dissolved in 60 ml of ethanol was stirred at room temperature for 30 minutes and then stirred at 50° C. for 90 minutes. The solvent was distilled off under reduced pressure, and 10% aqueous sodium hydroxide was added to the residue and the mixture was extracted with chloroform. After drying of the extract, chloroform was distilled off and the residue was purified by silica gel column chromatography (solvent: chloroform-methanol-triethylamine=20:1:0.1) to give 2.33 g of (E)-N-(2-nitrocinnamyl)-N'-(4-pyridyl)ethyenediamine as a yellow oily substance.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([C@H:25]([O:27][C:28]3[N:29]([CH3:39])[C:30]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)=[N:31][N:32]=3)[CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1.CI.[NH4+].[Cl-]>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([C:25]([CH3:1])([O:27][C:28]3[N:29]([CH3:39])[C:30]([C:33]4[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=4)=[N:31][N:32]=3)[CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@@H](Oc1nnc(-c2ccncc2)n1C)c1noc(-c2cccc(Cl)c2)n1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1c(OC(C)(C)c2noc(-c3cccc(Cl)c3)n2)nnc1-c1ccncc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a solution of diisopropylamine (55.0 ml, 0.39 mmol) in THF (3 ml) at 0° C. was added nBuLi (2.5M, hex., 135 ml) slowly. After 20 minutes the mixture was cooled to −78° C. and (−)-4-(5-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine (107 mg, 0.28 mmol) in THF (2 ml) was added. The resulting mixture was stirred for 45 minutes before CH3I (22 ml, 0.34 mmol) was added and the reaction mixture was stirred for 1 h at r.t. Sat. NH4Cl solution was added and the mixture was extracted with EA. The organic phase was washed with H2O and brine, dried and evaporated. Purification of the residue by silica gel chromatography using CHCl3:MeOH 50:1 followed by prep. HPLC gave the title compound (22 mg, 20%). 1H-NMR: 2.11 (s, 6 H) 3.63 (s, 3 H) 7.45 (d, 1 H) 7.52-7.57 (m, 1 H) 7.59 (d, 2 H) 7.98 (d, 1 H) 8.09 (s, 1 H) 8.72 (d, 2 H)
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([C:21]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24][NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:23]3[CH2:24][CH2:25][C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(C2(c3ccccc3)CCNC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2)(c2ccccc2)C1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 3,3-diphenylpyrrolidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 68% overall yield. FDMS m/e=412 (M+ of free base). mp 193°-194°. α[D]589 =-9.11 c=0.33, methanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[F:12].O=S(Cl)Cl.[CH3:17]N(C=O)C>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:17])=[O:10])=[CH:4][C:3]=1[F:12]
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccc(Br)c(F)c1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Br)c(F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 801.5 %

Procedure:
To a mixture of 2-(4-bromo-3-fluorophenyl)acetic acid (5 g, 21.46 mmol) in MeOH (50 mL) was added SOCl2 (1.879 mL, 25.7 mmol) and DMF (0.166 mL, 2.146 mmol). Then the mixture was stirred at 80° C. for 16 h. The mixture was concentrated and extracted with EA (100 mL×2) and washed with NaHCO3 (100 mL) to give the organic layer. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated to yield a brown oil of methyl 2-(4-bromo-3-fluorophenyl)acetate (5 g, 17.20 mmol, 80% yield): 1H NMR (400 MHz, MeOH-d4) δ 7.53 (t, J=7.6 Hz, 1H), 7.15 (dd, J=1.6, 9.6 Hz, 1H), 7.04-6.99 (m, 1H), 3.67 (s, 3H), 3.65 (s, 2H); ES-LCMS m/z 249.0 (M+H+2).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]([N:12]([CH3:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C>C1COCC1>[CH3:19][N:12]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:10][CH2:9][NH2:8]
Reactant: CN(C(=O)CN)c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CN(CCN)c1ccncc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
2-Amino-N-methyl-N-pyridin-4-yl-acetamide trifluoroacetate (182, 1.0 eq.) was dissolved in anhydrous THF (50 mL) under argon. A 1 M solution of LiAlH4 in THF (6.1 eq.) was added dropwise at rt and the reaction vessel was placed in an oil bath. The temperature was raised to 70° C. and the mixture stirred for 15 hr. The reaction mixture was cooled and quenched by the slow addition of water (5 mL). Solvents were evaporated to give a white solid which was titurated several times with ethyl acetate to give compound 183 as a colourless oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:12]=[N:11][C:10]([N:13]([CH2:21][C:22]3([C:26]4[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:25][CH2:24][CH2:23]3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)=[N:4][CH:3]=1.[NH:33]1[C:37](B(O)O)=[CH:36][CH:35]=[N:34]1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[NH:33]1[CH:37]=[CH:36][C:35]([C:2]2[S:6][C:5]([C:7]3[N:12]=[N:11][C:10]([N:13]([CH2:21][C:22]4([C:26]5[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=5)[CH2:25][CH2:24][CH2:23]4)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[CH:9][CH:8]=3)=[N:4][CH:3]=2)=[N:34]1
Reactant: OB(O)c1ccn[nH]1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(Br)s2)nn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(-c3cc[nH]n3)s2)nn1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 39.4 %

Procedure:
To a microwave vial was added t-butyl 6-(5-bromothiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (100 mg, 0.19 mmol), 1H-pyrazol-5-ylboronic acid (32 mg, 0.29 mmol), (dppf)PdCl2 (16 mg, 0.02 mmol), dioxane (2 mL), and K2CO3 (0.2 mL of a 2M aqueous solution, 38 mmol). The mixture was heated to 140° C. in a microwave reactor and stirred for 20 min. The reaction mixture was then poured into ethyl acetate (50 mL), washed with water (20 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAc/hex) to afford 38 mg of t-butyl 6-(5-(1H-pyrazol-3-yl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. This compound was dissolved in CH2Cl2 (5 mL) and TFA (1 mL). The reaction was stirred for 30 min at rt, concentrated, and then purified using reverse phase chromatography to give 15 mg of 6-(5-(1H-pyrazol-3-yl)thiazol-2-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine, (M+H=408.3).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[F:21][C:22]([F:35])([F:34])[C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[NH2:26]>ClCCl.N1C=CC=CC=1>[F:21][C:22]([F:34])([F:35])[C:23]1[CH:24]=[C:25]([NH:26][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:26][C:25]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:23]([C:22]([F:21])([F:34])[F:35])[CH:24]=2)=[O:13])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 8 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3,5-bis(trifluoromethyl)aniline (2.66 g, 11.6 mmol) in 21 mL of pyridine. The crude product was recrystallized from ethyl acetate-hexanes (1:9) to yield 0.34 g of the title compound, mp 213°-214° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:23][O:24][C:25]([C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2)=[O:26].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:23][O:24][C:25]([C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:31]2)=[O:26]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: COC(=O)c1cccc2c1CNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cccc2c1CN(c1c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 39.8 %

Procedure:
298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 257 mg of 4-methoxycarbonylisoindoline hydrochloride, 532 mg of DBU, and 2ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 181 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:11](=[S:13])[NH2:12])=[CH:5][CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].CC1C=CC=CC=1C.O(C(C)C)C(C)C>O>[NH2:12][C:11](=[S:13])[NH:10][N:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:14](=[O:16])[CH3:15]
Reactant: COc1ccc(NNC(N)=S)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1ccc(N(NC(N)=S)C(C)=O)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of 17.5 parts of 2-(4-methoxyphenyl)hydrazinecarbothioamide, 10 parts of acetic acid anhydride and 90 parts of dimethylbenzene is stirred and refluxed for one hour. The reaction mixture is allowed to cool to room temperature and 2,2'-oxybispropane and water are added. The precipitated product is filtered off and dried, yielding 14.5 parts (89%) of acetic acid 2-(aminothioxomethyl)-1-(4-methoxyphenyl)hydrazide.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][OH:50])=[CH:45][CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][OH:50])=[CH:45][CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CO)cc4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of Intermediate 5c (109 mg, 0.300 mmol) and Intermediate 33a (126 mg, 0.300 mmol) in 1,4-dioxane (3 mL) and DIPEA (78 μL, 0.45 mmol) was stirred at 80° C. for 3 h, and then at 95° C. for 2 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in DCM, to give the title compound as an off-white powder after freeze-drying (95 mg, 50%). LCMS (Method 5): Rt 3.26 min, m/z 635.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.81-2.26 (11H, m), 2.31-2.40 (1H, m) 3.10-3.17 (1H, m), 3.99 (1H, br t, J 8.1), 4.56 (2H, d, J 5.6), 4.78-4.87 (1H, m), 5.29 (1H, t, J 5.7), 5.37-5.42 (1H, m), 6.33 (1H, s), 7.11 (1H, d, J 8.7), 7.24-7.47 (9H, m), 7.75 (1H, d, J 9.7), 8.07 (1H, s), 8.24 (1H, br d).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH3:40][C:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[C:44]([CH3:55])[N:43]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([CH3:63])[CH:58]=2)[N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1.C(O)C.O>[CH3:40][C:41]1[C:45]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)=[C:44]([CH3:55])[N:43]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([CH3:63])[CH:58]=2)[N:42]=1
Reactant: Cc1cccc(Cn2nc(C)c(B3OC(C)(C)C(C)(C)O3)c2C)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(C)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 30.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (300 mg, 0.4 mmol) was coupled with (Intermediate 56A) 3,5-dimethyl-1-(3-methylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (163 mg, 0.5 mmol) in sodium carbonate (147 mg, 1.0 mmol), PdCl2(dppf) (17 mg, 0.02 mmol), toluene/ethanol/water (2/2/3 ml) to give 90 mg (28% yield) of titled compound.
Reaction SMILES: [P:1]([O:7]C)([O:5][CH3:6])([O:3][CH3:4])=[O:2].COC(=O)[O-].[CH3:14][NH+:15]1[CH2:19][CH:18]([CH3:20])[N:17]([CH3:21])[CH:16]1[CH3:22].O>CO>[CH3:4][O:3][P:1]([O-:7])([O:5][CH3:6])=[O:2].[CH3:14][NH+:15]1[CH2:19][CH:18]([CH3:20])[N:17]([CH3:21])[CH:16]1[CH3:22]
Reactant: COP(=O)(OC)OC
Agent: CC1C[NH+](C)C(C)N1C
Agent: COC(=O)[O-]
Solvent: CO
Solvent: O
Product: COP(=O)([O-])OC
Temperature: 100 °C
Reaction time: 20 h

Procedure:
By adding trimethyl phosphate (TMP, produced by Daihachi Chemical Industries Co., Ltd.) (0.1 mol) to a methanol solution of 1,2,3,4-tetramethylimidazolinium methyl carbonate salt (0.1 mol) obtained in the same manner as Example 1, adding water (0.3 mol) and stirring the mixture at 100° C. for 20 hours, the trimethyl phosphate was hydrolyzed and, at the same time, a salt exchange reaction was performed. As a result, a methanol solution of 1,2,3,4-tetramethylimidazolinium dimethyl phosphate monoanion was obtained. The resulting solution was heated at a pressure reduction degree of 1.0 kPa or less at 50° C., so that methanol was evaporated until methanol was no longer distilled off. By increasing the temperature from 50° C. to 100° C. and heating the mixture for 30 minutes to distill by-products off, an electrolyte (c5) {1,2,3,4-tetramethylimidazolinium dimethyl phosphate monoanion} was obtained. The yield was 99 wt %. The content of dimethyl phosphoric acid monoanion in the anions was 99% by mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C@H:23]([N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)[CH3:24])[CH:19]=[N:20][C:21]=3[F:22])[CH:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:21]1[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]3[CH:47]=[CH:48][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)[CH:10]=2)=[CH:17][C:18]([C@H:23]([N:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)[CH3:24])=[CH:19][N:20]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)nc(C)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCNCC4)cnc3F)nc(C)n2)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A mixture of tert-butyl 4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-1-piperazinecarboxylate (0.57 g, 0.87 mmol) in CH2Cl2 (4.3 mL) at 0° C. was treated with TFA (1.29 mL, 17.36 mmol). The reaction mixture was allowed to warm up to RT. After 90 minutes the reaction mixture was concentrated and the residue was dissolved in CH2Cl2 and saturated NaHCO3 (aq.). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 6-(2-fluoro-5-((1R)-1-(1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.41 g, 0.74 mmol, 85% yield). m/z (ESI, +ve) 557.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J=9.29, 2.45 Hz, 1H); 8.14-8.18 (m, 1H); 7.18 (d, J=7.43 Hz, 4H); 6.86 (d, J=8.61Hz, 4H); 6.83 (br. s, 1H); 4.74 (br. s., 4H); 3.79 (s, 6H); 3.57 (q, J=6.78 Hz, 1H); 2.96 (m, 4H); 2.62 (s, 3H); 2.57 (br. s., 2H); 2.44-2.51 (m, 2H); 1.40 (d, J=6.85 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])=[CH:5][C:4]=1[N:19]([CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[S:20]([CH3:23])(=[O:22])=[O:21]>CO.C(Cl)(Cl)Cl.[Pd]>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:19]([CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: COc1ccc(C(=O)OCc2ccccc2)cc1N(CCN1CCOCC1)S(C)(=O)=O
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(C(=O)O)cc1N(CCN1CCOCC1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
Benzyl 4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)benzoate (1.5 g, 3.34 mmol) was dissolved in MeOH (20 ml), then Pd/C 5% (0.33 mmol, 702 mg) was added, and the mixture was hydrogenated in a Parr apparatus (H2:35 psi) for 30 minutes. The reaction was diluted with CHCl3 (300 ml) and MeOH (300 ml) to dissolve the product that precipitated in MeOH, and the catalyst was filtered over a celite pad, and the solvent is evaporated under vacuum, to yield 700 mg of white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:11]2[CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]=[CH:9][N:10]=2)[S:5][CH:6]=1
Reactant: Cc1ccccc1Sc1ccnc(Cl)c1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1csc(Nc2cc(Sc3ccccc3C)ccn2)n1
Yield: 50.2 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (0.291 g, 2.55 mmol), 2-chloro-4-(o-tolylthio)pyridine (0.600 g, 2.55 mmol), potassium phosphate (0.595 g, 2.80 mmol), Pd2(dba)3 (0.117 g, 0.127 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.074 g, 0.127 mmol) were reacted to provide 4-methyl-N-(4-(o-tolylthio)pyridin-2-yl)thiazol-2-amine (0.401 g, 50% yield). 1H NMR (d6-DMSO) δ 11.04 (s, 1H), 8.07 (d, 1H), 7.57 (d, 1H), 7.47 (d, 2H), 7.34 (m, 1H), 6.63 (s, 1H), 6.50 (s, 1H), 6.48 (m, 1H), 2.34 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[CH2:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1>[Pd].C(OCC)(=O)C>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[NH2:11])([CH3:10])[CH3:9]
Reactant: C=C(C)c1ccc(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C)C)c(N)c1
Reaction time: 8 h

Procedure:
To 4-methyl-2-nitro-1-(prop-1-en-2-yl)benzene (0.986 g, 5.56 mmol) in a 100 mL round-bottomed flask equipped with a stir bar was added ethyl acetate (55.6 mL) and palladium on carbon (1.18 g, 0.556 mmol). The reaction was evacuated and backfilled with hydrogen (balloon). The reaction was stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through a pad of Celite® and concentrated providing the title compound as a clear and colorless oil (0.788 g, 95%): IR (thin film) 3464 (m), 3372 (m), 3011 (m), 2959 (s), 2869 (m), 1621 (m), 1575 (m), 1509 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J=7.8 Hz, 1H), 6.61 (dd, J=7.8, 1.7 Hz, 1H), 6.54-6.50 (m, 1H), 3.59 (bs, 2H), 2.87 (hept, J=6.8 Hz, 1H), 2.24 (s, 3H), 1.24 (d, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 143.14, 136.16, 129.82, 125.33, 119.79, 116.55, 99.97, 27.36, 22.41, 20.96.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C@@H:11]([CH3:25])[CH2:10]2)=[CH:4][CH:3]=1.[C:26]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][C@@H:11]1[N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH2:14][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:26]([O:34][CH2:35][CH3:36])=[O:33])=[CH:3][CH:4]=2)[CH2:10]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C[C@H]1CN(Cc2ccc(Br)cc2)CCN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(CN2CCN(C(=O)OCc3ccccc3)[C@@H](C)C2)cc1
Yield: 60.4 %

Procedure:
A mixture of D6 (1.62 g, 4 mmol), diethyl malonate (0.73 ml, 4.8 mmol), palladium (II) acetate (27 mg, 0.12 mmol), potassium phosphate (1.95 g, 2.3 mmol) and bis(1,1-dimethylethyl)(2′-methyl-2-biphenylyl)phosphane (83 mg, 0.264 mmol) in 1,4-dioxane (20 ml) were refluxed together under argon for ˜20 h. The mixture was filtered through Celite® and concentrated. Chromatography (0-40% EtOAc/hexane) gave the title compound as a clear oil (1.165 g). MS (ES): MH+ 483.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6](F)[C:5]([Br:13])=[CH:4][CH:3]=1.FC1C2C(=O)OC(=O)NC=2C=CC=1.[Cl:27]C1C2C(=O)OC(=O)NC=2C=CC=1>>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([Cl:27])[C:5]([Br:13])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reactant: CNC(=O)c1c(N)ccc(Br)c1F
Agent: O=c1[nH]c2cccc(F)c2c(=O)o1
Product: CNC(=O)c1c(N)ccc(Br)c1Cl

Procedure:
Prepared analogously to Compound 27D replacing 5-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (Compound 27E) with 5-Chloro-1H-benzo[d][1,3]oxazine-2,4-dione (Compound 28E). 1H NMR (CDCl3, 500 MHz) δ=2.95 (d, J=5.2 Hz, 3H), 6.02 (brs, 2H), 6.89 (d, J=8.8 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.79 (brs, 1H).