Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-].[Na+].[CH2:4]([O:6][C:7](=[O:17])[C:8]([CH2:15][CH3:16])(CC)P(O)(O)=O)C.[CH3:18]/[C:19](=[CH:22]\[CH2:23]CC)/C=O.O>CO>[CH3:1]/[C:16](=[CH:18]\[CH2:19][CH2:22][CH3:23])/[CH:15]=[CH:8]/[C:7]([O:6][CH3:4])=[O:17]
Reactant: CCOC(=O)C(CC)(CC)P(=O)(O)O
Reactant: C[O-]
Reactant: CCC/C=C(\C)C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC/C=C(C)/C=C/C(=O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 28 wt % solution of sodium methoxide in methanol (112.6 g) at 10° C. were added dropwise diethyl phosphonoacetic acid ethyl ester (110.75 g) and (E)-2-methyl-2-hexenal (50.36 g) successively under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 hours, poured into chilled water and extracted with dichloromethane. The extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give 74.88 g of crude methyl (E,E)-4-methyl-2,4-octadienoate as an oil. This oil was used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18](=[O:47])[CH2:19][NH:20][C:21]([C:23]1[CH:46]=[CH:45][C:26]2[N:27]([CH3:44])[C:28]([NH:30][C:31]3[S:32][C:33]4[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:34]=4[N:35]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:48][NH:49][CH3:50].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([C:14](=[O:15])[N:49]([CH3:50])[CH3:48])[NH:17][C:18](=[O:47])[CH2:19][NH:20][C:21]([C:23]1[CH:46]=[CH:45][C:26]2[N:27]([CH3:44])[C:28]([NH:30][C:31]3[S:32][C:33]4[CH:39]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:37]=[CH:36][C:34]=4[N:35]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C

Procedure:
[(S)-5-Dimethylcarbamoyl-5-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-pentyl]-carbamic acid tert-butyl ester (200 mg) was prepared by following General Procedure F starting from (S)-6-tert-butoxycarbonylamino-2-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-hexanoic acid (260 mg), 2 M dimethylamine in THF (1 mL), HBTU (400 mg), and DIEA (400 uL) in DMF (2 mL).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][OH:26])=[NH:24])=[C:21]([F:29])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:47](OC1C=CC=CC=1)=[O:48]>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:34][CH:35]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]2[NH:24][C:47](=[O:48])[O:26][N:25]=2)=[C:21]([F:29])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(NO)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCOCc3ccccc3)cc2F)no1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 0.62 g of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-N-hydroxy-benzamidine in 17 mL of dichloromethane at 0° C., under argon, were added 0.23 mL of pyridine and 154 μL of phenyl chloroformate. The reaction mixture was stirred for 10 min at 0° C. followed by 1 h at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was taken up into 10 mL of acetonitrile under argon and 0.165 mL of 1,4-diazabicyclo[5.4.0]undec-7-ene (DBU) was added. The reaction mixture was stirred at room temperature overnight then warmed to 40° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up into dichloromethane and a 1M aqueous solution of NaH2PO4 was added. The aqueous layer was separated and extracted three times with dichloromethane. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 770 mg of crude product as a yellow powder. Purification by column chromatography on silica gel (heptane 1/ethyl acetate 1) gave 150 mg followed by column washing with 100% MeOH gave 320 mg of the title compound. In total, 470 mg of 3-{4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-[1,2,4]oxadiazol-5-one as white powder was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH3:19])=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([OH:17])=O)[CH:10]=2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:18][CH3:19])=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[O:17])[CH:10]=2)=[N:6][CH:7]=1
Reactant: CNc1nc(Nc2cc(C(=O)O)nn2C)ncc1Cl
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1nc(Nc2cc(C(=O)N3CCOCC3)nn2C)ncc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 100 mL round bottom flask equipped with a stir bar was added 0.116 g of 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylic acid, 0.19 g of o-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate, 0.14 mL of diisopropylethylamine and 2 mL of dimethylformamide. After pre-activating for 10 minutes, 0.05 mL of morpholine was added and the reaction stirred at room temperature for 2 hours. The reaction was concentrated and purified by preparative reverse phase HPLC to yield 53.2 mg of (5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazol-3-yl)(morpholino)methanone. LCMS (Method A): [MH+]=352.0 at 2.80 min. 1H-NMR (DMSO): δ 9.47 (s, 1H), 7.86 (s, 1H), 7.15 (s, 1H), 6.78 (s, 1H), 3.74 (s, 3H), 3.61 (m, 8H), 2.88 (d, 3H). K1=0.16.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:11][C:12]1([F:26])[CH2:17][CH2:16][N:15]([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C([O:29][C:30]([CH2:32][C:33](O)=[O:34])=O)C.C(=O)(OC)OC(C)(C)C[N+]#[C-].CC(C)([O-])C.[Na+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:22]([C:21]4[CH:24]=[CH:25][C:18]([N:15]5[CH2:16][CH2:17][C:12]([F:26])([F:11])[CH2:13][CH2:14]5)=[CH:19][CH:20]=4)[C:30](=[O:29])[CH2:32][C:33]3=[O:34])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)CC(=O)O
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=Cc1ccc(N2CCC(F)(F)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [C-]#[N+]CC(C)(C)OC(=O)OC
Agent: [Na+]
Product: O=C1CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(N2CCC(F)(F)CC2)cc1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.890 g, 6.69 mmol), 4-(4,4-difluoropiperidin-1-yl)benzaldehyde (1.5 g, 6.69 mmol), 2-(ethoxycarbonyl)acetic acid (0.883 g, 6.69 mmol), 1-isocyano-2-methylpropan-2-yl methyl carbonate (1.05 g, 6.69 mmol) and sodium tert.-butoxide (0.713 g, 6.35 mmol) according to method 3.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.CC1(C)C(C)(C)[O:15][B:14](B2OC(C)(C)C(C)(C)O2)[O:13]1.C([O-])(=O)C.[K+].C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[ClH])(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([B:14]([OH:15])[OH:13])=[CH:10][C:6]=2[N:7]=[CH:8]1
Reactant: Clc1ccc2ocnc2c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Product: OB(O)c1ccc2ocnc2c1
Temperature: 80 °C

Procedure:
A mixture of 5-chlorobenzoxazole (0.129 g, 0.84 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.4956 g, 1.95 mmol), potassium acetate (0.41 g, 4.2 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene hydrochloride (43 mg, 0.10 mmol) and palladium acetate (11 mg, 0.05 mmol) was degassed, treated with tetrahydrofuran (10 mL) and the resulting mixture heated at 80° C. overnight. The mixture was diluted with water (100 mL), acidified to pH 6 and extracted with EtOAc (3×40 mL). The extracts were washed with water, dried and concentrated in vacuo. The residue so obtained was purified by chromatography over silica gel eluting with DCM to 10% MeCN/DCM to afford 1,3-benzoxazole-5-boronic acid, pinacol ester. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37-1.39 (m, 12 H) 7.59 (d, J=8.34 Hz, 1 H) 7.86 (dd, J=8.08, 1.01 Hz, 1 H) 8.10 (s, 1 H) 8.26 (s, 1 H); MS (ES+): m/z 246.23 [MH+].
Reaction SMILES: [S:1](=[O:4])([OH:3])[O-:2].[Na+].[CH2:6]=[O:7].C=O>>[CH2:6]=[O:7].[S:1]([O-:4])([O-:3])=[O:2].[S:1]([O-:7])([O-:3])(=[O:2])=[O:4]
Reactant: O=S([O-])O
Agent: C=O
Agent: [Na+]
Product: O=S(=O)([O-])[O-]
Product: O=S([O-])[O-]

Procedure:
Formaldehyde sodium bisulfite is a true chemical compound, not a mixture of two chemicals. For example, when formaldehyde is mixed with a proteinaceous material as described in U.S. Pat. No. 3,942,969, Mar. 9, 1976, volatile formaldehyde may be detected from this mixture; whereas no volatile formaldehyde is detected from the chemical compound formaldehyde sodium bisulfite. This chemical compound produces a slow release of formaldehyde only by the oxidation of the "sulfite" to the "sulfate."
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([CH3:23])[CH:3]=1.[CH3:24][C@H]1CN(CC2C=CC(NC)=CC=2)CCN1C(OC(C)(C)C)=O.[BH4-].[Na+]>>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:24])=[CH:3][C:4]=2[CH3:23])[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: Cc1cc(N)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(C)c1
Temperature: 50 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-[(4-amino-2-methylphenyl)methyl]-2-methyl-1-piperazinecarboxylate (D80) using a method similar to that described for D3 in Description 3A although the reaction was heated at 50° C. for 16 h prior to addition of sodium borohydride and 5.5 h after addition. δH (CDCl3, 400 MHz) 7.00 (1H, d), 6.45 (1H, d), 6.39 (1H, dd), 4.17 (1H, br.s), 3.76 (1H, d), 3.57 (1H, br.s), 3.33 (1H, d), 3.27 (1H, d), 3.01 (1H, td), 2.82 (3H, s), 2.71 (1H, d), 2.58 (1H, d), 2.32 (3H, s), 2.11 (1H, dd), 1.90 (1H, m), 1.45 (9H, s), 1.17 (3H, d). MS (AP+): 356.2 (MNa+), 234.2, no molecular ion (MH+) observed.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.C[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH2:25][CH2:24][CH2:23]2.CC1CC2C(=CC=CC=2)N1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:29][CH:28]=2)[CH2:23][CH:25]1[CH3:24])=[O:9]
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: O=C(O)c1ccccc1Oc1cc(Cl)ccc1Cl
Agent: CC1Cc2ccccc2N1
Product: CC1Cc2ccccc2N1C(=O)c1ccccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 31, Step 2, replacing 2-(2,5-dichloro-phenoxy)-nicotinic acid with 2-(2,5-dichloro-phenoxy)-benzoic acid (Example 110, Step 1) and 6-methyl-1,2,3,4-tetrahydro-quinoline with 2-methyl-2,3-dihydro-1H-indole ([CAS RN 6872-06-6]). MS (ISP): 398.2 [M+H]+.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH3:17])[C:10]([C:18]([O:20]CC)=[O:19])=[CH:9]2)([O-:5])=[O:4].O.Cl>CS(C)=O>[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH3:17])[C:10]([C:18]([OH:20])=[O:19])=[CH:9]2)([O-:5])=[O:4]
Reactant: CCCn1c(C(=O)OCC)cc2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCn1c(C(=O)O)cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C

Procedure:
236 mg (3.68 mmol, 85% pure) of potassium hydroxide (powder) are initially charged in 10 ml of dimethyl sulphoxide, 961 mg (3.48 mmol) of the compound from Example I are added and the mixture is stirred at RT for half an hour. The reaction mixture is poured into about 100 ml of water and with cooling, 10% strength hydrochloric acid is added a little at a time to the solution until no more precipitate is formed. The precipitated solid is filtered off with suction and dried in a desiccator under reduced pressure overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:19][CH2:18][CH2:17][C:16]3[C:15](=[NH:20])[NH:14][C:13](=N)[C:12]2=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:22].[CH3:23][O:24][C:25]1[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=1[NH:27][C:28]1[S:29][CH2:30][C:31](=[NH:33])[N:32]=1.N=C1C2CCCCC=2C(=N)N1.Cl.N=C1NC(=N)CS1>>[ClH:22].[NH:20]=[C:15]1[C:16]2[CH2:17][CH2:18][CH2:19][CH:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:12]=2[C:13](=[C:30]2[S:29][C:28]([NH:27][C:26]3[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=3[O:24][CH3:23])=[N:32][C:31]2=[NH:33])[NH:14]1
Reactant: COc1ccccc1NC1=NC(=N)CS1
Reactant: COc1ccc(C2CCCC3=C2C(=N)NC3=N)cc1OC
Agent: Cl
Agent: N=C1CSC(=N)N1
Agent: N=C1NC(=N)C2=C1CCCC2
Product: COc1ccccc1NC1=NC(=N)C(=C2NC(=N)C3=C2C(c2ccc(OC)c(OC)c2)CCC3)S1

Procedure:
When equivalent amounts of 4-(3,4-dimethoxyphenyl)-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(o-methoxyanilino)-4-imino-2-thiazoline hydrochloride are substituted for the 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazolidine hydrochloride respectively, in the procedure described in Example 10, part A above, there is obtained as the product 1-imino-4-(3,4-dimethoxyphenyl)-4,5,6,7-tetrahydro-3-[2-(o-methoxyanilino)-4-imino-2-thiazolin-5-ylidene]isoindoline hydrochloride.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f23) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[N:4]([CH2:10][CH2:11][CH3:12])[C:5](=O)[NH:6][C:7]=1[NH2:8].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[CH:27]=[C:26]([C:28](O)=[O:29])[CH:25]=[N:24]2)[CH:19]=[CH:20][CH:21]=1.Cl.CN(C)CCCN=C=NCC.C[OH:46]>>[NH2:8][C:7]1[NH:6][CH2:5][N:4]([CH2:10][C:11](=[O:46])[CH3:12])[C:3](=[O:13])[C:2]=1[NH:1][C:28]([C:26]1[CH:25]=[N:24][N:23]([CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:32])[F:31])[CH:17]=2)[CH:27]=1)=[O:29]
Reactant: O=C(O)c1cnn(Cc2cccc(C(F)(F)F)c2)c1
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Reactant: CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(=O)CN1CNC(N)=C(NC(=O)c2cnn(Cc3cccc(C(F)(F)F)c3)c2)C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 5,6-diamino-3-propyl-1,3-dihydropyrimidine-2,4-dione (2.3 g, 126 mmol) and 1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-carboxylic acid (3.79 g, 14 mmol) in methanol (50 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.67 g, 14 mmol), and the reaction mixture was stirred for 3 days at room temperature (although less time is acceptable). The precipitate was filtered off, and was washed sequentially with water, and methanol. The product was dried under vacuum to provide N-(6-amino-2,4-dioxo-3-propyl(1,3-dihydropyrimidin-5-yl))(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)carboxamide, a compound of formula (13).
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH:11]([C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][CH:15]=1)([CH3:13])[CH3:12].[OH-].[Na+]>ClC(Cl)C.O>[CH:11]([C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][C:15]=1[CH:4]=[O:5])([CH3:13])[CH3:12]
Reactant: Cc1cc(C(C)C)c[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1cc(C(C)C)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
To a solution of anhydrous DMF (2.1 ml, 27 mmol) in anhydrous dichloroethane (50 ml) at 0° C. under nitrogen, POCl3 (2.1 ml, 23 mmol) was added dropwise. The solution was allowed to warm at room temperature for 1 h. Then, the suspension was cooled at 0° C. and a solution of 3-isopropyl-5-methylpyrrole (2 g, 16 mmol) in dichloroethane (20 ml) was added dropwise over 20 min. After stirring at room temperature for 24 h, water followed by NaOH were added to pH: 8. The organic layer was extracted, dried and the solvent removed to dryness. The residue was purified by flash chromatography. Yield 67%, m.p. 90–93° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:25]=3)[N:21]=[N:20]2)=[CH:15][CH:14]=1)=[O:12]>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[Br:8][CH2:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:25]=[C:24]2[C:22]1[N:21]=[N:20][N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:14][CH:15]=2)[CH:23]=1
Reactant: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(C)cc34)nn2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(CBr)cc34)nn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
Zirconium tetrachloride (23 mg; 0.10 mmol; 0.1 eq.) was added in one portion to a solution of NBS (160 mg; 0.90 mmol; 0.9 eq.) in DCM (10 mL) at 0° C. A solution of tert-butyl 3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-methyl-1H-indazole-1-carboxylate (434 mg; 1.00 mmol; 1.0 eq.) in DCM (10 mL) was then added dropwise to the reaction mixture which was subsequently stirred at RT for 16 h. The reaction mixture was then diluted with DCM and washed sequentially with saturated NaHCO3 and brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow solid (392 mg, 76%) 1H NMR (300 MHz, DMSO) δ 9.70 (s, 1H), 8.62 (d, J=1.0 Hz, 1H), 8.30 (d, J=8.8 Hz, 2H), 8.21 (d, J=8.8 Hz, 2H), 8.16 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.8 Hz, 1.7, 1H), 4.99 (s, 2H), 3.92 (s, 3H), 1.70 (s, 9H). MS (ESI+): 512.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([O-])=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]([C:14](=[O:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17])[CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: CCOC(=O)C(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1CCc2cc(O)ccc2C1=O
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To 6-hydroxy-1-tetralone (10.4 g, 0.064 mol) and ethyl oxalate (17.4 mL, 0.128 mol) in THF (100 mL) was added dropwise lithium bis(trimethylsilyl)amide (1M in THF, 130 mL). The slurry was stirred overnight and a solid was filtered. The solid was dissolved in water and made acidic to pH 2.5 with 3 N HCl, precipitating a waxy solid. The waxy solid was extracted into EtOAc, dried (MgSO4), and concentrated in vacuo leaving a dark solid (15.7 g). The solid was purified by chromatography on silica gel, eluting with 15% EtOAc/hexanes to give a yellow solid (5.9 g). The solid was recrystallized from EtOAc/hexanes to give the product as a yellow solid, 3.7 g (22% yield). FABHRMS m/z 263.0925 (M+H, C14H15O5 requires 263.0919). 1H NMR (CDCl3/300 MHz) 7.93 (d, 1H); 6.80 (d of d, 1H); 6.68 (s, 1H); 5.72 (s, 1H); 4.39 (q, 2H); 3.00-2.75 (m, 4H); 1.40 (t, 3H).
Reaction SMILES: [B].[CH2:2]([CH:4]1[O:6][CH2:5]1)Cl.[CH2:7]([OH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:2]([O:15][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:4]1[O:6][CH2:5]1
Reactant: CCCCCCCCO
Reactant: ClCC1CO1
Agent: [B]
Product: CCCCCCCCOCC1CO1
Temperature: 0 °C
Yield: 111.8 %

Procedure:
Octanol (130 g) and 2.84 g of a boron trifluorideether complex were cooled to 0° C. while stirring. At a temperature maintained at 0° C., 138.8 g of epichlorohydrin was added dropwise over 1 hour. After completion of dropwise addition, an excess alcohol was distilled off at 100° C. under reduced pressure (13 to 26 Pa). The reaction mixture was cooled to 50° C. and while maintaining the temperature at 50° C., 125 g of a 48% aqueous solution of sodium hydroxide was added dropwise over 1 hour. After stirring for 3 hours, 200 mL of water was added to the reaction mixture to cause separation. The water layer thus obtained was removed and then the residue was washed twice with 100 mL of water, whereby 208 g of crude octyl glycidyl ether was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[OH:14])(=O)[CH3:2].C(O)(=O)C>CO.[C].[Pd]>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[OH:14])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(NC(C)=O)cc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.8 %

Procedure:
To a solution of N-(4-acetyl-3-hydroxyphenyl)acetamide (4.0 g, 20.7 mmol) in methanol (50 mL)/acetic acid (50 mL) was added 10% palladium-carbon powder (2.0 g), and the mixture was stirred at room temperature for 6 hr under a hydrogen atmosphere of 2.8 pressure. 10% Palladium-carbon powder was filtered off by celite filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was washed with diisopropyl ether/hexane (1:1) to give the title compound (3.07 g, 83%) as a colorless powder.