Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][N:5]=1)=O.CS(C1N=C(C2NN=CC=2C2C=CC=CC=2)C=CN=1)(=O)=O.[CH3:42][C:43]1[CH:44]=[C:45]([CH:47]=[C:48]([CH3:50])[CH:49]=1)[NH2:46]>>[CH3:42][C:43]1[CH:44]=[C:45]([NH:46][C:4]2[N:9]=[C:8]([C:10]3[NH:14][N:13]=[CH:12][C:11]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]=[CH:6][N:5]=2)[CH:47]=[C:48]([CH3:50])[CH:49]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: CS(=O)c1nccc(-c2[nH]ncc2-c2ccccc2)n1
Agent: CS(=O)(=O)c1nccc(-c2[nH]ncc2-c2ccccc2)n1
Product: Cc1cc(C)cc(Nc2nccc(-c3[nH]ncc3-c3ccccc3)n2)c1
Temperature: 90 °C

Procedure:
A mixture of 2-(methylsulfinyl)-4-(4-phenyl-1H-pyrazol-5-yl)pyrimidine and 2-(methylsulfonyl)-4-(4-phenyl-1H-pyrazol-5-yl)pyrimidine (3-4, 3-5, 186 mg, 0.62 mg,) and 3,5-dimethylaniline (2 mL, excess) was heated at 90° C. for 24 hours. The reaction mixture was purified by flash chromatography. Elution with CH2Cl2 to 30% EtOAc/CH2Cl2 gave N-(3,5-dimethylphenyl)-4-(4-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine (3-6) as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.26 (d, 1H, J=5 Hz), 7.66 (s, 1H), 7.38–7.44 (m, 5 H), 7.21 (br s, 2H), 7.04 (br s, 1H), 6.75 (br s, 1H), 6.71 (d, 1H, J=5 Hz), 2.34 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([O:16]CC2C=CC=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cc2ccc(F)cc2c(O)c1C
Yield: 81.9 %

Procedure:
To a stirred solution of (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (15.8 g, 46.7 mmol) in MeOH (150 mL) was added 10% palladium on carbon (2.4 g). The resulting mixture was vigorously stirred under a balloon of hydrogen overnight. The reaction mixture was filtered through celite. The filtrate was concentrated to give the crude product, which was purified by silica gel chromatography (10% ethyl acetate in hexanes) to yield (6-fluoro-4-hydroxy-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (9.5 g, 82%) as a white solid. MS calcd. for C14H14FO3 [(M+H)+] 249, obsd. 249.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[C:13]([O:16][CH2:17][C:18](Cl)=[O:19])(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][CH2:17][C:18]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1)=[O:19])(=[O:15])[CH3:14]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cccc2sc(N)nc12
Solvent: c1ccncc1
Product: COc1cccc2sc(NC(=O)COC(C)=O)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-4-methoxybenzothiazole (4.5 g) is dissolved in pyridine (80 ml) and thereto is added dropwise acetoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water and then with diethyl ether, dried and recrystallized from ethanol to give the title compound (4.3 g) having the following physical properties.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[Li]CCCC.[C:18](=[O:20])=[O:19].[OH-].[Na+]>C1COCC1.C(OCC)C>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:18]([OH:20])=[O:19])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=C=O
Reactant: Clc1nccc2ccc(Br)cc12
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1ccc2ccnc(Cl)c2c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
To a suspension of 7-bromo-1-chloroisoquinoline (2.000 g, 8.247 mmoles) in THF (12 mL) and diethyl ether (12 mL) cooled down to −78° C. was added n-BuLi (3.96 mL, 9.9 mmol, 2.5M in hexanes). Stirred for five minutes and then bubbled carbon dioxide while venting with a needle for approximately one minute. The reaction mixture was warmed up to 0° C. and 15 mL of a 1N aqueous sodium hydroxide were added. The mixture was diluted with diethyl ether stirred for 18 h. The organic and aqueous layers were separated and the organics were washed with 1N aqueous sodium hydroxide and water. The aqueous fractions were combined and acidified to pH 4 with 1N aqueous hydrochloric acid. The resulting solids were collected by filtration and dried to give the title compound (1.252 g, 73%). +ESI (M+H) 208.1 1H NMR (400 MHz, DMSO-d6) d ppm 13.58 (br. s., 1H) 8.86 (m, 1H) 8.43 (d, J=5.67 Hz, 1H) 8.33 (dd, J=8.61, 1.57 Hz, 1H) 8.19 (d, J=8.41 Hz, 1H) 8.01 (dd, 1H)
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>C(O)C.[OH-].[Na+]>[ClH:1].[CH2:12]([N:14]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: CCNCC
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)Cc1ccc(C(=O)O)cc1
Product: Cl
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To a solution of 4-chloromethylbenzoic acid (17.1 g, 0.1 mol) in ethanol (200 ml) cooled in an ice bath was added dropwise diethylamine (32.2 g, 0.44 mol) over 20 minutes. The reaction mixture was refluxed for 17 hours, cooled to room temperature and the solvent was stripped. The residue was dissolved in 1N NaOH (50 ml), extracted with ether (50-100 ml) and the aqueous layer was acidified with 2N HCl to a pH of 3. The aqueous layer was stripped and the residue was treated with ethanol, filtered and the ethanol was stripped. The residue was recrystallized from isopropyl alcohol (3×) to afford 13.54 g of 4-diethylaminomethyl benzoic acid hydrochloride, m.p. 189-191° C.
Reaction SMILES: C1C2C(CO[C:16]([N:18](C)[C:19]([CH3:69])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:33]([O:63][CH3:64])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:61][CH3:62])[C@@H:43]([CH3:60])[C:44]([NH:46][C@H:47]([C:55]3[S:56][CH:57]=[CH:58][N:59]=3)[CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[S:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl.C(NCC)C.CO>[CH3:16][NH:18][C:19]([CH3:69])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:33]([O:63][CH3:64])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:61][CH3:62])[C@@H:43]([CH3:60])[C:44]([NH:46][C@H:47]([C:55]1[S:56][CH:57]=[CH:58][N:59]=1)[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[S:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CCNCC
Solvent: ClCCl
Solvent: CO
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC)C(C)C
Yield: 94.6 %

Procedure:
According to general procedure A, from #83 (552 mg, 0.555 mmol, 1 eq.) in dichloromethane (10 mL, 0.05 M) and diethylamine (10 mL) was synthesized the crude desired material, which was diluted with methanol, concentrated in vacuo onto silica, and purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give #84 (406 mg, 95%) as a white solid. LC-MS: m/z 772.8 [M+H+], retention time=1.35 minutes; HPLC (Protocol A): 774.4 [M+H+], retention time=7.390 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.54 (br d, J=8 Hz) and 10.81 (br d, J=8 Hz), total 1H], 7.78-7.84 (m, 2H), [7.65 (d, J=3.1 Hz) and 7.69 (d, J=3.3 Hz), total 1H], 7.29-7.34 (m, 2H), 7.20-7.28 (m, 2H), 7.14-7.19 (m, 1H), 6.27-6.35 and 6.40-6.48 (2 m, total 1H), [4.51 (dd, J=9, 8 Hz) and 4.57 (dd, J=9, 8 Hz), total 1H], 3.24 and 3.25 (2 s, total 3H), 3.16 and 3.21 (2 s, total 3H), 2.94 and 3.00 (2 br s, total 3H), 2.09 and 2.10 (2 s, total 3H), 1.08 and 1.09 (2 s, total 3H), 0.73-0.80 (m, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.O.O.[NH2:17][NH2:18]>O>[CH3:1][CH:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[N:17][NH2:18]
Reactant: CC(C)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: NN
Solvent: O
Product: CC(C)C(=NN)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a partially dissolved solution of 2-methyl-1-(3-nitrophenyl)-1-propanone (Preparation 55, 1.0 g, 5.2 mmol) in industrial methylated spirits (6 ml) was added dropwise hydrazine hydrate monohydrate (0.5 ml, 10.4 mmol). The reaction mixture was refluxed for 16 h, before cooling to room temperature and pouring into ice and water (50:50, 15 ml) giving a very fine white precipitate in a yellow solution. The mixture was extracted with diethyl ether (2×50 ml), the combined organic extracts were washed with brine and dried (MgSO4), before concentrating to give an amber oil. The crude product was purified by chromatography on silica gel eluting with dichloromethane:ethyl acetate (19:1) to give the title compound as a mixture of cis and trans hydazones (0.54 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1I.CCN(C(C)C)C(C)C.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: Fc1cncc(Cl)c1I
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cncc(Cl)c1N1CCNCC1
Temperature: 120 °C

Procedure:
In a 100 mL sealed reaction vessel/bomb, 3-chloro-5-fluoro-4-iodo-pyridine (5600 mg, 21.75 mmol) was taken up in NMP (12 mL). To the resulting clear brown solution was added DIPEA (3.373 g, 4.546 mL, 26.10 mmol) followed by piperazine (2.810 g, 32.62 mmol). The vessel was sealed and heated thermally at 120° C. for 18 hrs. The mixture was allowed to cool to RT and was concentrated in vacuo to afford a brown gum which was purified by chromatography on silica, eluting with a gradient of DCM-DCM:MeOH:NH3(90: 10:1) 100-0 to 0:100. Fractions containing clean product were collected and concentrated in vacuo to afford 1-(3-chloro-5-fluoropyridin-4-yl)piperazine as a cream solid. (3.52 g, 75%). MS (ES+) 216.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5]([N:8]=CN(C)C)=[N:6][CH:7]=1.[CH3:37][N:38]([CH3:48])[C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1>>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][C:46]([NH:45][C:42]2[CH:43]=[CH:44][C:39]([N:38]([CH3:48])[CH3:37])=[CH:40][CH:41]=2)=[O:47])=[CH:7][N:6]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: COc1cc(-c2csc3c(N)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(NC(=O)Nc4ccc(N(C)C)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(7-amino-4-{[(dimethylamino)methylene]amino }thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide and 4-(dimethylamino)phenyl isocyanate using General Procedure N followed by General Procedure M. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 8.48 (s, 1H), 8.11 (s, 1H), 7.99 (d, 1H), 7.95 (s, 1H), 7.71 (d, 1H), 7.59 (d, 1H), 7.55 (s, 1H), 7.35 (s, 1H), 7.29 (m, 3H), 7.21 (m, 1H), 7.15 (t, 1H), 7.08 (d, 1H), 6.70 (d, 2H), 5.39 (br, 2H), 4.04 (s, 3H), 3.92 (s, 3H), 2.83 (s, 6H); MS: (MH)+606.
Reaction SMILES: [F:1][CH:2]([F:9])[C:3](=[O:8])[CH2:4][C:5](=O)[CH3:6].O.[NH2:11][NH2:12]>O1CCCC1>[F:1][CH:2]([F:9])[C:3]1([OH:8])[NH:12][N:11]=[C:5]([CH3:6])[CH2:4]1
Reactant: NN
Reactant: CC(=O)CC(=O)C(F)F
Solvent: C1CCOC1
Solvent: O
Product: CC1=NNC(O)(C(F)F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,1-difluoropentane-2,4-dione (2.5 g, 0.018 mol) in tetrahydrofuran (32 mL) was added hydrazine hydrate (0.98 mL, 0.020 mol) in tetrahydrofuran (32 mL) dropwise. The reaction was stirred at 25° C. for 16 hours and then concentrated in vacuo. The residue was used in the next reaction without further purification. 1H NMR (CDCl3): δ 5.68-5.96 (t, 1H), 5.50-5.80 (br s, 1H), 2.98 (dd, 1H), 2.68 (dd, 1H), 2.01 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:10]2[N:9]=[N:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].CC1C=C(C)C=C(C)N=1.Cl>CO>[CH3:17][O:18][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Clc1cccc2c1nnn2C1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cccc2c1nnn2C1CCCCC1

Procedure:
A slurry of 1.5 g. of 4-chloro-1-cyclohexylbenzotriazole, 15 g. of sodium methoxide, 10 g. cuprous iodide in 50 ml. of 2,4,6-trimethyl pyridine and 10 ml. of methanol is heated to the reflux temperature for 26 hours. The reaction is cooled and poured into 150 ml. of 10% hydrochloric acid. The product is extracted with ethyl ether and on evaporation of the solvent, 0.5 g. of an oil was obtained which solidified on standing. Recrystallized the crude product from ethyl ether, m.p. 118°-120° C. The analytical sample has a m.p. 133°-134° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:8][O:9][C:10]1[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1.[F:19][C:20]([F:31])([F:30])[C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[F:19][C:20]([F:30])([F:31])[C@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]([N:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[CH2:8][O:9][C:10]2[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:28])[CH2:25][CH2:26]1
Reactant: NC(=O)c1ncccc1OC[C@H]1CCCN1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Agent: Cl
Product: NC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride (EXAMPLE 1 Step 3) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[NH2:21][C:22]1[CH:26]=[CH:25][N:24]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[N:23]=1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:21][C:22]3[CH:26]=[CH:25][N:24]([CH2:27][C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])[N:23]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1ccn(CC(=O)N2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccn(CC(=O)N4CCOCC4)n3)nn12

Procedure:
Into a microwave vial, 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.150 g, 0.000522 mol), 2-(3-Amino-pyrazol-1-yl)-1-morpholin-4-yl-ethanone (0.241 g, 0.00115 mol), 1-Methoxy-2-propanol (1.26 mL, 0.0128 mol) and N,N-Diisopropylethylamine (0.200 mL, 0.00115 mol) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 7% methanol). The collected fraction afforded a yellow solid (62 mg, 27%). LCMS (E/I+) 434.8 (M+H). MP 179-182° C. NMR 1H (DMSO-d6)-9.54 (s, 1H), 8.90 (s, 1H), 7.82 (dd, 1H, JJ=1.60, 7.70 Hz), 7.40-7.49 (m, 2H), 7.18 (d, 1H, J=8.23 Hz), 7.08 (t, 1H, J=7.64 Hz), 6.92 (d, 1H, J=4.70 Hz), 6.88 (, d, 1H, J=4.70 Hz), 6.43 (d, 1H, J=1.76 Hz), 3.78 (s, 3H), 3.52-3.62 (m, 4H), 3.39-3.52 (m, 4H), 3.30 (s, 3H).
Reaction SMILES: [NH2:1][C:2](=[O:32])[C@H:3]([NH:8][C:9]1[CH:18]=[C:17]([C:19]#[N:20])[C:12]([C:13]([O:15]C)=O)=[C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=2)[N:10]=1)[CH2:4][CH:5]([CH3:7])[CH3:6]>CO.CC(O)=O.[OH-].[OH-].[Pd+2]>[CH3:6][CH:5]([CH3:7])[CH2:4][C@@H:3]([NH:8][C:9]1[N:10]=[C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:23]=2)[C:12]2[C:13](=[O:15])[NH:20][CH2:19][C:17]=2[CH:18]=1)[C:2]([NH2:1])=[O:32]
Reactant: COC(=O)c1c(C#N)cc(N[C@H](CC(C)C)C(N)=O)nc1Nc1cccc(S(C)(=O)=O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C[C@@H](Nc1cc2c(c(Nc3cccc(S(C)(=O)=O)c3)n1)C(=O)NC2)C(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.4 %

Procedure:
A mixture of (R)-methyl 6-(1-amino-4-methyl-1-oxopentan-2-ylamino)-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (73.2 mg, 0.159 mmol) and palladium hydroxide on carbon (23.2 mg, 0.165 mmol) in MeOH (6 mL) and HOAc (3 mL) was stirred at RT for 12 h under a hydrogen atmosphere. The mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure. The residue was treated with saturated aq NaHCO3 (20 mL) and MeOH (20 mL). The resulting mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was treated with saturated aq NaHCO3 (30 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from EtOH to give the title compound as a white solid (18.8 mg, 27%). 1H-NMR (DMSO-d6) δ ppm 0.87-0.94 (m, 6H), 1.54-1.63 (m, 2H), 1.76 (br s, 1H), 3.32 (s, 3H), 4.24 (s, 2H), 4.50 (br s, 1H), 6.17 (s, 1H), 7.00-7.04 (m, 2H), 7.22 (br s, 1H), 7.47-7.57 (m, 2H), 8.01 (br s, 1H), 8.06 (s, 1H), 8.45 (br s, 1H), 9.23 (s, 1H). [M+H] calc'd for C20H26N5O4S, 432; found, 432.5.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>C(O)(C)C.C(O)C>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:4]4[C:5]5[C:24](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH2:23][CH2:22][CH2:21]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1.[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:11]4[C:10]5[C:24](=[CH:17][CH:18]=[CH:13][CH:14]=5)[CH2:23][CH2:22][CH2:21]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCCc2ccccc21
Yield: 65.7 %

Procedure:
A stirred mixture of N-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.41 g, 8.73 mmol), 1,2,3,4-tetrahydroquin 3line (1.33 g, 10 mmol, in isopropyl alcohol (50 ml) was heated at reflux for 6 hours. The solution was cooled and the solvent was removed on a rotary evaporator. The crude solid was purified by flash chromatography over a silica gel column (SiO2, 40 g, eluted with methylene chloride DCM, and 1-3% MeOH in DCM). The product thus purified weighed 2.0 g. This material was dissolved in ethanol and was treated with a solution of fumaric acid (567 mg, 1.0 eq) in ethanol. The solids collected were recrystallized again from ethanol (50 ml) to yield 1.0 g of white crystals, as a hemifumarate, m.p. 170°-171° C.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][C@H:5]([OH:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].S(O)(O)(=O)=O.[NH2:21][CH2:22][CH3:23].C1(C)C=CC=CC=1>O.CO>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C@H:5]1[O:15][CH2:23][CH2:22][NH:21][CH2:4]1
Reactant: COc1ccccc1C[C@@H](O)CCl
Reactant: CCN
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccccc1C[C@@H]1CNCCO1
Temperature: 40 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
Powdered sodium hydroxide (7.2 g, 180 mmol) was dissolved in water (15 mL). The solution was allowed to cool to ambient temperature before addition of intermediate (a) (R)-1-chloro-3-(2-methoxyphenyl)-2-propanol(6.0 g, 30.0 mmol) in methanol (20 mL+2×5 mL washes) via dropping funnel. After stirring for 5 mins 2-aminoethane hydrogen sulfate (16.9 g, 120 mmol) was added in portions over 5 mins and the reaction mixture heated to 40° C. After 2 hrs, toluene (75 mL) and powdered sodium hydroxide (7.2 g, 180 mmol) were added and the reaction heated to 65° C. and stirred for 17 hrs. The mixture was cooled, diluted with water (300 mL) and extracted with toluene (2×150 mL). The combined organics were washed with water (slowly separating emulsion obtained) and brine, dried (Na2SO4) and concentrated under reduced pressure to afford the crude product as a pale yellow oil (5.21 g). Purification by column chromatography (silica: ethyl acetate/ethanol/triethylamine, 79/20/1 ratio) afforded intermediate (d), (R)-2-(2-methoxybenzyl)morpholine as a colorless oil (6.04 g, 50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:17][NH2:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:18][CH3:17])=[O:10])[CH2:6]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2Cl)C1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2ccc(Cl)cc2Cl)C1
Reaction time: 5 h

Procedure:
A stirred solution of 4.8 g (0.017 mole) of 3-(2,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 4 mL (0.05 mole) of 40% aqueous monomethylamine. After stirring for 5 h, the reaction mixture was diluted with 200 mL of water and the precipitated solid collected by filtration (4.6 g). The crude product was recrystallized from acetonitrile yielding 3.4 g (72.7%) of coarse white powder, mp 140°-141° C.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:13]([N:15]([CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(CC)Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of methyl 4-formylbenzoate (300 mg) in 1,2-dichloroethane (6 mL) is added diethylamine (113 μL), and thereto is added sodium triacetoxyborohydride (581 mg) and acetic acid (261 μL) under ice-cooling. The mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with chloroform (5 mL) and thereto is added a saturated sodium hydrogencarbonate solution (10 mL). After stirring, the organic layer is separated and concentrated. The resultant crude product is purified by column chromatography on NH-silica gel (Solvent; n-hexane:ethyl acetate=70:30→40:60) to give methyl 4-(diethylaminomethyl)benzoate (144 mg, yield; 60%) as an oil. MS (APCI) m/z: 222 [M+H]+