Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28](OCC)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 110 and was obtained as a white solid: 1H NMR (CDCl3) δ 10.18 (1H, br t, J=5 Hz), 8.54 (1H, d, J=1 Hz), 7.15 (2H, dd, J=9, 5 Hz), 7.07 (1H, s), 7.02 (2H, t, J=9 Hz), 4.88 (2H, s), 4.11 (2H, s), 3.64 (2H, m), 3.57 (2H, m), 3.51 (2H, m), 3.45 (2H, m), 3.39 (3H, s), 2.03 (2H, m), 1.90 (2H, m); HRMS calcd for C25H27FN4O5+H+: 483.2044. Found: 483.2055.
Reaction SMILES: [C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([O-:32])=[O:31].[C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][NH+:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)C(F)(F)F
Reactant: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: C[NH+]1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: O=C([O-])C(F)(F)F
Yield: 93.6 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and trifluoroacetic acid (0.31 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium 2,2,2-trifluoroacetate as a crystalline white solid (1.22 g, 93% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]2=[N:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][N:11]2[N:10]=1)#N.[OH2:23].[OH:24]P(O)(O)=O>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]2=[N:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][N:11]2[N:10]=1)([OH:24])=[O:23]
Reactant: O=P(O)(O)O
Reactant: O
Reactant: N#Cc1ccccc1-c1nn2cc(-c3ccccc3)nc2s1
Product: O=C(O)c1ccccc1-c1nn2cc(-c3ccccc3)nc2s1

Procedure:
12 g of 2-(2-cyanophenyl)-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazole (Example No. 31) are heated to 170°-175° C. in 40 g of crystalline H3PO4 for 5 hours, the mixture is cooled and stirred with water, the precipitate is filtered off and dissolved in 2 N NaOH, the solution is clarified with charcoal and the product is precipitated with 2 N HCl.
Reaction SMILES: ClC1N=[C:4](NC2C=C(C=CC=2)C(O)=O)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2N=1.[NH2:21][C:22]([NH2:24])=[O:23].C.[OH-:26].[Na+]>>[N:21]1[C:6]2[CH:8]=[CH:9][S:10][C:5]=2[C:4]([OH:26])=[N:24][C:22]=1[OH:23]
Reactant: NC(N)=O
Reactant: O=C(O)c1cccc(Nc2nc(Cl)nc3c2SCC3)c1
Reactant: [OH-]
Agent: [Na+]
Product: Oc1nc(O)c2sccc2n1
Reaction time: 2 h
Yield: 75 %

Procedure:
10.0 g (64.0 mmol) of methylester 3-aminothiophene-2-carboxylate (I) and 19.0 g (31.60 mmol) of urea are mixed and melted for 2 hours at 200° C. After cooling, the reaction mixture is dissolved in 1 molar sodium hydroxide solution and decolorized with activated charcoal. It is filtered and the filtrate is cooled and acidified with 4M hydrochloric acid. The precipitate formed is suction filtered and dried. 8.03 g of product II (75%) is obtained as a powder.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C@@H:33]3[C@@H:37]([OH:38])[CH2:36][CH2:35][NH:34]3)[N:26]=2)[N:4]=1)[CH3:2].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:43](C)=O.[Na+]>CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C@@H:33]3[C@@H:37]([OH:38])[CH2:36][CH2:35][N:34]3[CH3:43])[N:26]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(OC[C@H]3NCC[C@@H]3O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCc1nn(Cc2cccc(OC[C@@H]3[C@@H](O)CCN3C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To N-(3-ethyl-1-((6-(((2R,3S)-3-hydroxypyrrolidin-2-yl)methoxy)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (5 mg, 0.0098 mmol; prepared as in Example 36) in MeOH (1 mL) was added HCHO as a 35% aqueous solution (16 mg, 0.20 mmol) and NaBH(OAc)3 (10 mg, 0.049 mmol). The reaction mixture was stirred for 30 minutes, concentrated under reduced pressure and purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to provide the final product (4 mg). MS (ES+APCI) m/z=526 (M+H).
Reaction SMILES: [N:1]1([C:10]2[C:11]3[CH:18]=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[C@H:9]2[C@H:4]([NH:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29]>C(#N)C.CN(C1C=CN=CC=1)C.CS(C)=O>[CH3:29][CH:28]([S:31]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:9]2[N:1]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:2][CH2:3][C@@H:4]12)(=[O:33])=[O:32])[CH3:30]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: c1nc(N2CC[C@H]3NCCC[C@H]32)c2cc[nH]c2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CC#N
Product: CC(C)S(=O)(=O)N1CCC[C@@H]2[C@H]1CCN2c1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-[(3aR,7aR)-octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine (12 mg, 0.049 mmol) in acetonitrile (493 tip was added DMAP (9.0 mg, 0.074 mmol) and DIPEA (17 μL, 0.099 mmol) followed by isopropylsulfonyl chloride (12 mg, 0.049 mmol). The reaction mixture was stirred for 20 hours at room temperature before being diluted with 1.0 mL DMSO and purified by mass-triggered reverse-phase HPLC using a Waters X-bridge Prep C18 column (5 micron, 19×100 mm), eluting with an ACN/water gradient (0.1% formic acid as modifier) to afford 4-{(3aR,7aR)-4-[(1-methylethyl)sulfonyl]octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl}-7H-pyrrolo[2,3-d]pyrimidine. LRMS calc'd for C16H24N5O2S [M+H]+, 350.2; found 350.2. 1H NMR (500 MHz, DMSO-D6) δ 11.6 (s, 1H); 8.04 (s, 1H); 7.09 (s, 1H), 6.51 (s, 2H); 4.29 (br s, 2H); 3.97-3.64 (br m, 21-1); 3.53 (d, 2H, J=11Hz); 3.38-3.34 (m, 1H); 3.02 (t, 1H. J=10Hz); 2.01 (br s, 1H); 1.64 (s, 1H), 1.62 (br s, 1H), 1.24-1.54 (br m, 2H). 1.21 (t, 6H, J=5.5Hz). Jak1 activity: ++
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(O)c(NC(=O)OC(C)(C)C)c1
Reactant: CN(C)CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(OCCCN(C)C)c(NC(=O)OC(C)(C)C)c1
Reaction time: 12 h

Procedure:
To a stirred, cooled (about 0° C.) solution of (2-hydroxy-5-methyl-phenyl)-carbamic acid tert-butyl ester (447 mg, 2.0 mmol), triphenyl phosphine (525 mg, 2.0 mmol), and 3-(dimethylamino)-1-propanol (237 μL, 2.0 mmol) in dry tetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (394 μL, 2.0 mmol) in 1 mL of tetrahydrofuran). After stirring for 12 hours, the reaction was diluted with 30 mL of ethyl acetate and washed with 30 mL of 10% aqueous sodium carbonate (2×30 mL), brine (1×30 mL), then dried (MgSO4) and filtered. The filtered solution was concentrated under reduced pressure to provide the desired crude product.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[C:6]=1[CH3:28])([CH3:4])([CH3:3])[CH3:2].IB1C2CCCC1CCC2>ClCCl.CCCCC>[C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N:16]([CH:25]([CH3:26])[CH3:27])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:6]=1[CH3:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(N(c2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)C(C)C)cc1
Agent: IB1C2CCCC1CCC2
Solvent: ClCCl
Solvent: CCCCC
Product: Cc1c(N(c2ccc(O)cc2)C(C)C)cc2c(c1C(C)(C)C)OCC2(C)C
Yield: 131.1 %

Procedure:
Following general procedure M and using 7-t-butyl-5-[isopropyl-(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 57, 0.032 g, 0.083 mmol) and 1M solution of 9-iodo-9-borabicyclo[3.3.1]nonane (B-iodo-9-BBN) in hexanes (0.2 mL, 0.2 mmol) in 0.6 mL of anhydrous dichloromethane and 1 mL of n-pentane, the title compound (0.04 g) was obtained as a brown oil that was used in the next step without further purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:32][CH3:33])[CH:4]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:43])=O>C(OCC)(=O)C>[Cl:43][CH2:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:32][CH3:33])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Yield: 67.4 %

Procedure:
To a mixture of methyl 5-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methanesulfonyloxybenzoate (0.20 g) and toluene (10 mL) was added thionyl chloride (0.055 g), and the mixture was heated under reflux for 1 hr. After concentration of the reaction mixture, ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methanesulfonyloxybenzoate (0.14 g, yield 67%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 146-147° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1>>[Cl-:2].[Cl-:2].[CH3:7][C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cc1ccc(C(=O)c2ccccc2)cc1
Product: [Cl-]

Procedure:
The reaction was proceeded by the method described in Example 1. 20.8G of PCl5 was reacted with 19.6 g of 4-methylbenzophenone to give 22.9 g(purity 87%, yield 79%) of 4-methylbenzophenone dichloride as a pale yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:16]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[C:21]([CH:28]([CH3:30])[CH3:29])[C:20]=1[S:31](Cl)(=[O:33])=[O:32])([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[C:21]([CH:28]([CH3:30])[CH3:29])[C:20]=1[S:31]([NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9]1)(=[O:33])=[O:32])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](N)C1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)N[C@H]2CCC[C@@H](NC(=O)OC(C)(C)C)C2)c(C(C)C)c1

Procedure:
Compound 7b was prepared following procedures similar to those described previously in Example 1, step A, substituting 7a for i-2d and 2,4,6-triisopropylbenzenesulfonyl chloride for i-5f, respectively. m/z (ES) 503 (MH+Na)+
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H]4CCCNC4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H:43]4[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]4)C(F)=CN=3)=CNC2=NC=1.C(N(C(C)C)CC)(C)C.[CH:59]1([C:63](Cl)=[O:64])[CH2:62][CH2:61][CH2:60]1>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][CH:44]4[CH2:43][CH2:48][CH2:47][CH2:46][N:45]4[CH:61]4[CH2:62][CH:59]([CH:63]=[O:64])[CH2:60]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: O=C(Cl)C1CCC1
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=CC1CC(N2CCCCC2Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.04 g, 0.11 mmol) in CH2Cl2 (1.40 mL) and DMF (300 g was added N,N-diisopropyl-N-ethylamine (0.30 mL, 1.70 mmol) followed by cyclobutanecarbonyl chloride (0.01 g. 0.12 mmol). The reaction mixture was allowed to stir at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 395.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C@H:11]1[CH2:16][NH:15][C:14]2[CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[CH:20][C:13]=2[N:12]1[C:31](=[O:33])[CH3:32].[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>ClCCl>[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39]([N:15]1[CH2:16][C@H:11]([CH3:10])[N:12]([C:31](=[O:33])[CH3:32])[C:13]2[CH:20]=[N:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[CH:17][C:14]1=2)=[O:40]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)N1c2cnc(-c3ccc(S(C)(=O)=O)cc3)cc2NC[C@@H]1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1c2cnc(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)c2ccco2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
N,N-Diisopropylethylamine (0.3 mL, 1.718 mmol) was added to a solution of (S)-1-(3-methyl-7-(4-(methylsulfonyl)phenyl)-2,3-dihydropyrido[4,3-b]pyrazin-4(1H)-yl)ethanone (0.004 g, 0.012 mmol) and furan-2-carbonyl chloride (0.2 mL, 2.029 mmol) in dichloromethane (1.0 mL), and the mixture stirred at room temperature for 2 h. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-1-(1-(furan-2-carbonyl)-3-methyl-7-(4-(methylsulfonyl)phenyl)-2,3-dihydropyrido[3,4-b]pyrazin-4(1H)-yl)ethanone (0.0038 g, 75%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.13-1.22 (m, 3 H), 2.25 (br s, 1 H), 2.31 (s, 3 H), 3.02 (s, 3 H), 3.88 (br s, 1 H), 4.05-4.18 (m, 1 H), 5.03 (br s, 1 H), 6.55 (dd, J=3.52, 1.76 Hz, 1 H), 7.20-7.26 (m, 1 H), 7.45 (dd, J=1.76, 0.88 Hz, 1 H), 7.78 (s, 1 H), 7.89-8.02 (m, 4 H). MS (ESI, pos. ion) m/z 440.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:5]=[C:4]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][N:21]=2)(=[O:19])=[O:18])[C:3]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37].O.[NH2:39][NH2:40].C(O)(=O)C>CN(C)C=O.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH:39][NH2:40])=[NH:15])[CH:9]=2)[N:5]=[C:4]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][N:21]=2)(=[O:19])=[O:18])[C:3]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Reactant: NN
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C(=N)NN)c2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Temperature: 15 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
122 g (233 mmol) of 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-2-(2-cyano-pyridine-4-yl)-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-amide was suspended in 450 ml of N,N-dimethyl formamide and the mixture was cooled down to 15° C. At this temperature, 35 ml of hydrazine hydrate were added dropwise within 1 hr. The resulting solution was stirred at 15° C. to 20° C. for 16 hr and thereafter diluted with 600 ml of de-ionized water. Then 50 ml of glacial acetic acid were added dropwise at 0° C. to 5° C. until pH=5.5. 600 g of ice were added and the suspension was stirred for 1 hr. The solid was filtered off under suction, washed with 3000 ml of water and dried at 40° C., 2000 Pa for 24 hr. There were obtained 126 g (97% of theory) of 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-2-[2-(hydrazino-imino-methyl)-pyridine-4-yl]-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-amide with a HPLC purity of 91.8% (w/w).
Reaction SMILES: [O:1]=[C:2]1[CH:12]=[N:11][C:10]2=[C:13]3[N:3]1[CH2:4][C@@H:5]([CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1)[N:6]3[C:7](=[O:14])[CH:8]=[CH:9]2.[ClH:30]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:30].[ClH:30].[NH2:22][CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][C@H:5]2[N:6]3[C:13]4[N:3]([C:2](=[O:1])[CH:12]=[N:11][C:10]=4[CH:9]=[CH:8][C:7]3=[O:14])[CH2:4]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of 1,1-dimethylethyl (1-{[(1R)-3,8-dioxo-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylen-1-yl]methyl}-4-piperidinyl)carbamate (76 mg, 0.189 mmol) in chloroform (2 ml) at room temperature was treated with 4M HCl in 1,4-dioxane (2 ml). A solid precipitated out and the mixture was stirred room temperature. After 0.5 h the reaction was complete so some methanol was added to dissolve most of the solid, followed by toluene and all the solvents were removed to afford the product as a dark yellow solid (70.9 mg, 99%).
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[CH:20]/[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@:17]1([CH2:18][OH:19])[CH2:1][C@H:20]1[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)[CH3:22]
Reactant: CC[Zn]CC
Reactant: C/C(=C/C(C)c1cccc(C)c1)CO
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1cccc([C@H](C)[C@@H]2C[C@]2(C)CO)c1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 9.4 g, 0.0114 mol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −15° C. Chloroiodomethane (4.02 g, 22.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between −15 and −20° C. After completion of the dropwise addition, the mixture was stirred at −10 to −15° C. for 20 minutes, and then cooled to −25° C. (Z)-2-Methyl-4-(3-methylphenyl)pent-2-en-1-ol (1.09 g, 5.7 mmol) was added dropwise at −20 to −25° C. over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at −15 to −25° C. for 40 minutes. Next, a 20% aqueous sulfuric acid solution (4.2 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1S*,2S*)-1-Methyl-2-((R*)-1-(3-methylphenyl)ethyl)cyclopropyl]methanol (0.83 g, 4.1 mmol, 70% yield) was obtained as the main isomer, and [(1S*,2S*)-1-methyl-2-((S*)-1-(3-methylphenyl)ethyl)cyclopropyl]methanol (0.20 g, 0.99 mmol, 17% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][C:15]([O:17]CC)=O)[CH:7]=[CH:6]2.[NH2:21][NH2:22]>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[CH2:14][C:15](=[O:17])[NH:21][N:22]=1)[CH:7]=[CH:6]2
Reactant: CCOC(=O)CC(=O)c1ccc2cc(OC)ccc2c1
Reactant: NN
Solvent: CC(=O)O
Product: COc1ccc2cc(C3=NNC(=O)C3)ccc2c1

Procedure:
Ethyl 3-(6-methoxy-2-naphthyl)-3-oxopropanoate (5.0 g, 18.3 mmol) and anhydrous hydrazine (0.63 ml 20 mmol) were refluxed in HOAc (100 ml) for 3 hours. Solvent was removed under reduced pressure, and the residue was washed with DCM and collected by filtration to give 5-(6-methoxy-2-naphthyl)-2,4-dihydro-3H-pyrazol-3-one as an off-white solid. This compound exists in the enol form in DMSO. NMR (500 MHz, DMSO-d6) δ: 3.87 (s, 3H); 5.95 (s, 1H); 7.17 (dd, J=2.7 Hz, 9.0 Hz, 1H); 7.31 (d, J=2.7 Hz, 1H); 7.74˜7.84 (m, 3H); 8.11 (br s, 1H); 9.66 (br s, 1H); 12 (br, 1H). MS C14H12N2O2 Cald: 240.09, Obsd: (M+1) 241.08.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.S([O-])([O-])(=O)=[O:14].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+].C(O)(C)C>CC(C)=O.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:14])[CH2:7][C:8]2([CH3:12])[CH3:11]
Reactant: O=S(=O)([O-])[O-]
Reactant: CC1(C)CCc2ccc(Cl)cc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC1(C)CC(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-chloro-1,1-dimethylindane (2.19 g, 0.0121 mol) was dissolved in acetone (50 mL), and 1.41 M solution of magnesium sulfate in water (9.02 mL) was added, followed by potassium permanganate (3.83 g, 0.0242 mol). The mixture was stirred at room temperature overnight. 1:1 water:isopropanol was then added to the mixture and this was stirred for 1 hour. The mixture was then evaporated to an aqueous residue and ethyl acetate was added. The mixture was filtered, washing the collected solids with EtOAc, and the filtrates were separated. The organic phase was concentrated, and the residue was purified by silica gel chromatography, eluting with 20 to 100% dichloromethane in hexanes to yield the product, 1.25 g (46%). 1H-NMR (400 MHz, CDCl, δ) 7.62 (d, J=8.3 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.34 (dd, J=1.8 Hz, 8.1 Hz, 1H), 2.60 (s, 2H), 1.42 (s, 6H).