Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])(C)C)=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:26]1COC[CH2:27]1>[Pt]>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][CH2:21][CH2:24][CH2:26][CH3:27])=[CH:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NC/C=C/c1cnc(-c2cccc(CO)c2)nc1
Agent: [Pt]
Product: CCCCOC(=O)NCCCc1cnc(-c2cccc(CO)c2)nc1

Procedure:
280 mg (0.82 mmol) of tert-butyl {(E)-3-[2-(3-hydroxymethylphenyl)pyrimidin-5-yl]allyl}carbamate are dissolved in 10 ml of THF, shaken at room temperature for 17 h with 300 mg of platinum on active carbon (5%, comprises 56% of water) under a hydrogen atmosphere. The catalyst is filtered off with suction, and the filtrate is evaporated to dryness.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:33]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:38][C:36]1[CH:37]=[C:32]([CH3:31])[N:33]=[C:34]([C:39]2([NH:42][C:24]([C:23]3[CH:27]=[CH:28][C:29]([CH3:30])=[C:21]([C:18]4[CH:19]=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=5[CH:17]=4)[CH:22]=3)=[O:25])[CH2:40][CH2:41]2)[N:35]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: Cc1cc(C)nc(C2(N)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nc(C)cc(C)n5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.5 mmol, 1 eq), 1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (0.203 g, 1.2 mmol, 2.5 eq) (60% purity), HOBT (0.068 g, 0.5 mmol, 1.1 eq), EDC.HCl (0.105 g, 0.55 mmol, 1.1 eq) in DCM at ambient temperature under a nitrogen atmosphere was added diisopropylehtylamine (0.194 g, 1.5 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally purified by preparative HPLC. Yield: 0.15 g (14%). 1H NMR (400 MHz, DMSO-d6): δ 1.24-1.27 (m, 2H), 1.53-1.56 (m, 2H), 2.30 (s, 3H), 2.32 (s, 6H), 2.82 (d, J=4.8 Hz, 3H), 7.00 (s, 1H), 7.38-7.44 (m, 4H), 7.59 (d, J=1.2 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.82-7.84 (s and d, 2H), 7.98-8.02 (m, 2H), 8.47-8.50 (m, 1H), 9.14 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[S:9])[CH3:2].C(C(CC)(CC)C([O-])([O-])[O-])C.[C:21]([O:24][C:25](=O)[CH3:26])(=O)[CH3:22]>>[CH2:21]([O:24][C:25](=[C:6]1[S:5][C:4](=[S:9])[N:3]([CH2:1][CH3:2])[C:7]1=[O:8])[CH3:26])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCN1C(=O)CSC1=S
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Product: CCOC(C)=C1SC(=S)N(CC)C1=O

Procedure:
A mixture of 5 g. (0.033 m.) of 3-ethylrhodanine, 12 ml. of triethylorthoacetate and 35 ml. of acetic anhydride is heated under reflux for 18 hours and the solution is then concentrated in vacuo. The cooled residue is filtered and the solid is dissolved in ether. The ether solution is washed with water, dried and evaporated in vacuo to give 5-(1'-ethoxyethylidene)-3-ethylrhodanine. The latter (3.6 g.) is stirred with 15 ml. of dioxane, 15 ml. of water and 15 ml. of 10% sodium hydroxide solution for 4 hours. The resulting solution is concentrated in vacuo at 40°C. and the aqueous solution is washed with ether, decolorized, then made acidic with dilute hydrochloric acid. The precipitate is dissolved in 10% sodium hydroxide solution, washed with ether and the aqueous solution is made acidic with dilute hydrochloric acid to give the product, 3-ethyl-5-(1'-hydroxyethylidene)-rhodanine, m.p. 93°C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([S:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[N:10]=1.C(=O)([O-])[O-].[K+].[K+].N1C=NC=NC=1.Br[CH2:49][CH2:50][CH2:51][CH3:52]>O.CN(C)C=O>[CH2:49]([O:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:7][CH2:2][CH2:3][CH3:4])=[CH:17][C:16]=3[OH:22])[N:12]=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[N:10]=2)=[C:2]([OH:1])[CH:7]=1)[CH2:50][CH2:51][CH3:52]
Reactant: CCCCBr
Reactant: Oc1ccc(-c2nc(-c3ccc(Sc4ccccc4)cc3)nc(-c3ccc(O)cc3O)n2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ncncn1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(-c2nc(-c3ccc(Sc4ccccc4)cc3)nc(-c3ccc(OCCCC)cc3O)n2)c(O)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a 500 mL round bottomed flask equipped with a magnetic stirrer, condenser and nitrogen atmosphere are charged 2.0 g (4.2 mmol) of 2,4-bis-(2,4-dihydroxyphenyl)-6-[4-(phenylthio)phenyl]-s-triazine, 0.58 g (4.2 mmol) of potassium carbonate and 30 mL of N,N-dimethylformamide. The mixture is heated to 90° C., and the s-triazine compound dissolves readily. Bromobutane (4.5 mL, 42.0 mmol) is added all at once. The reaction mixture is heated at 90° C. for 2.5 hours and then stirred at room temperature overnight yielding a yellow precipitate. Chilled water is added and the yellow precipitate is isolated by vacuum filtration to give 2.74 g of crude product. The crude product is purified by flash chromatography with 1:1 heptane:ethyl acetate to afford 0.26 g (10%) yield of the title compound as a yellow solid; mp>250°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH:31]1[C:43]2[CH:42]([CH2:44]O)[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:44][CH:42]5[C:43]6[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=6[C:36]6[C:41]5=[CH:40][CH:39]=[CH:38][CH:37]=6)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: OCC1c2ccccc2-c2ccccc21
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OCC5c6ccccc6-c6ccccc65)cc4CCC3C2C2CCCC2)cc1Cl

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and 9-fluorenylmethanol according to Method E. 1H NMR (400 MHz, CDCl3) δ ppm 1.19-1.67 (m, 7H), 1.72-1.85 (m, 1H), 1.99 (ddd, J=26.11, 12.96, 4.16 Hz, 1H), 2.07-2.22 (m, 1H), 2.25-2.38 (m, 1H), 2.85-3.03 (m, 1H), 3.06-3.21 (m, 1H), 3.50 (ddd, J=13.83, 9.26, 4.83 Hz, 1H), 4.41 (t, J=7.12 Hz, 1H), 4.60-4.70 (m, 3H), 7.03 (dd, J=8.73, 2.01 Hz, 1H), 7.29-7.38 (m, 3H), 7.40-7.51 (m, 3H), 7.66 (d, J=7.52 Hz, 2H), 7.82 (d, J=7.52 Hz, 2H), 7.91-8.00 (m, 2H), 8.20 (d, J=8.06 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([O:16][CH2:17][C:18]2([C:28]#[N:29])[CH:25]3[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:27][CH:19]2[CH2:20]4)[CH2:24]3)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:30]1(B(O)O)[CH2:32][CH2:31]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.CC(O)=O.CC(O)=O.[Pd].O>[C:28]([C:18]1([CH2:17][O:16][C:3]2[C:2]([CH:30]3[CH2:32][CH2:31]3)=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([F:15])[CH:4]=2)[CH:25]2[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]3)[CH2:24]2)#[N:29]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a solution of tert-butyl 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoate (1.12 g, 2.66 mmol) in toluene (40 mL) was added water (5 mL), cyclopropylboronic acid (1.32 g, 15.40 mmol), tribasic potassium phosphate (1.69 g, 7.94 mmol), tricyclohexylphosphine tetrafluoroborate (0.658 g, 2.13 mmol) and palladium(II) acetate trimer (0.25 g, 1.09 mmol) while degassing with argon. The reaction mixture was heated to reflux under an argon atmosphere for 16 hours, cooled to ambient temperature. The mixture was filtered through a pad of diatomaceous earth that was washed with ethyl acetate (100 mL). The filtrate was diluted with ethyl acetate (100 mL), washed with a 3:1 mixture of saturated aqueous ammonium chloride and water (150 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of 0-10% ethyl acetate in hexanes to afford the title compound as a yellow foamy solid (1.01 g, 89%): 1H NMR (300 MHz, CDCl3) δ 7.41 (d, J=8.3 Hz, 1H), 6.51 (d, J=12.2 Hz, 1H), 4.26 (s, 2H), 2.36-2.27 (m, 4H), 2.08-2.00 (m, 2H), 1.91-1.87 (m, 5H), 1.78-1.73 (m, 4H), 1.56 (s, 9H), 0.94-0.87 (m, 2H), 0.64-0.59 (m, 2H); MS (ES−) m/z 426.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1Br)[C:45]#[N:46]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:49]5[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][C:42]=5[CH3:41])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1cc(C#N)ccc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C#N)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (300 mg) and 3-methyl-4-bromobenzonitrile (120 mg) instead of 4-bromobenzoic acid methyl ester used in Example 1-D-8, in the same manner as Example 1-D-07, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-benzonitrile was obtained, and then the PMB groups were removed according to the above Deprotection method 3 using 54 mg of the crude product, to obtain the desired compound (D-234) as an ivory powder (32 mg, 94%).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[C:25]([F:26])=[CH:24][N:23]=[C:22]4[N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:28]=[CH:29][C:21]=34)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.O1CCOCC1>C1COCC1>[F:26][C:25]1[C:20]([C:18]2[CH:17]=[N:16][N:15]([C:4]3([CH2:3][C:1]#[N:2])[CH2:7][NH:6][CH2:5]3)[CH:19]=2)=[C:21]2[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:37])[CH3:35])[C:22]2=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3c(F)cnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)c(F)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.7 %

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (3.05 g, 5.79 mmol) in THF (40 mL) was added a 4.0 M solution of hydrogen chloride in 1,4-dioxane (70 mL, 280 mmol). The mixture was stirred at room temperature for 2 hours and concentrated to give 3.08 g (99.2%) of {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile.2[HCl] as a yellowish solid. LC/MS found: 427.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: COCCOc1cc2c(Cl)ncnc2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COCCOc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC
Temperature: 70 °C

Procedure:
According to the procedure described in Example 50, a mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (0.201 g, 0.73 mmol) from Example 1A, 4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline (0.195 g, 0.73 mmol) from the previous step, and Cs2CO3 (0.261 g, 0.8 mmol) in isopropanol (10 mL) was heated at 70° C. for 7 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-6-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea as a solid. 1H NMR (300 MHz, CDCl3) δ 9.13 (br and s, 2H), 8.61 (s, 1H), 7.62 (s, 1H), 7.55 (s, 1H), 7.31 (m, 3H), 6.97 (dd, 1H), 6.08 (s, 1H), 4.34 (t, 2H), 4.11 (s, 3H), 3.89 (t, 2H), 3.49 (s, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z 508 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:24][CH:23]=1
Reactant: COc1cc2c(=O)[nH]c3nccc(Cl)c3c2cc1OC
Reactant: Nc1ccc(Cl)cc1
Product: COc1cc2c(=O)[nH]c3nccc(Nc4ccc(Cl)cc4)c3c2cc1OC
Yield: 30.8 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 212 using Compound 211 (50 mg, 0.17 mmol) and 4-chloroaniline (29 mg, 0.22 mmol) to provide 213 (20 mg, 30% yield) as a white solid. LC-MS (M+H=382, obsd.=382).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH:10]([CH2:23][C:24]([OH:26])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CO.[Pd]>[O:26]=[C:24]1[NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH:10]2[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2[N+](=O)[O-])C(CC(=O)O)C1
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The product of Example 22C (658 mg, 1.801 mmol) was dissolved in methanol (50 mL) and 10% Pd/C (52 mg) was added. The flask was evacuated and purged with nitrogen (3 cycles) and then with hydrogen (3 cycles), and the reaction was stirred at room temperature under hydrogen (1 atm) for 7 hours. The flask was evacuated and purged with nitrogen (3 cycles), and the reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated under vacuum, and the residue was dissolved in tetrahydrofuran (25 mL). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (680 mg, 1.788 mmol) and diisopropylethylamine (1 mL) were added, and the mixture was stirred at room temperature for 14 hours and then concentrated under vacuum. The residue was purified by chromatography (SiO2, eluted with hexanes-ethyl acetate, 100:0-50:50) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 2.18 (d, J=13.5 Hz, 1H), 2.74 (dd, J=13.3, 6.9 Hz, 1H), 2.88-3.30 (m, 5H), 4.01-4.19 (m, 2H), 6.93-6.98 (m, 1H), 7.01-7.10 (m, 2H), 7.16 (s, 1H), 7.17-7.24 (m, 1H); MS (DCI) m/z 318 (M+H)+.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]Cl)[N:31]=1>CN(C)C=O>[Cl:29][C:30]1[N:31]=[C:32]([CH2:36][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: ClCc1cccc(Cl)n1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4cccc(Cl)n4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloro-6-chloromethyl-pyridine (34.3 mg, 0.21 mmol) described in Manufacturing Example 52-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacefic acid) to obtain the title compound (15.9 mg, 37%) as a trifluoroacetic acid salt.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:27]=1[CH2:28]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:28][C:27]3[C:26]([F:25])=[CH:33][C:32]([F:34])=[CH:31][C:30]=3[F:35])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Fc1cc(F)c(CCl)c(F)c1
Product: Fc1cc(F)c(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c(F)c1
Yield: 34.5 %

Procedure:
The title compound (0.027 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2,4,6-trifluorobenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C20H17ClF3N3, 391.11. found, m/z 392.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.30-7.26 (m, 4H), 6.80-6.78 (br m, 2H), 5.25 (s, 2H), 2.94-2.92 (m, 4H), 2.82-2.80 (m, 2H), 2.66-2.62 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH3:21])[CH:12]=1)=[O:10]>>[CH2:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9](=[O:10])[CH2:6][C:2]#[N:1])=[CH:12]1)[CH3:21]
Reactant: Nc1cc[nH]n1
Reactant: CCn1cc(C(=O)OC)c2ccccc21
Product: CCn1cc(C(=O)CC#N)c2ccccc21
Yield: 91 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1bis) from 1-ethyl-1H-indole-3-carboxylic acid methyl ester (860.0 mg, 4.2 mmol, 1.0 eq). 820.0 mg of the title product (yield 91%) were obtained and used directly for the next step.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[CH3:13][NH:14][C:15]([NH2:17])=[O:16]>CN(C=O)C.CCCCCC.CCOC(C)=O>[CH3:13][NH:14][C:15]1[O:16][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:17]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CNC(N)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CNc1nc(-c2ccc(C#N)cc2)co1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
Dissolve 4-cyanophenacyl bromide (10 g, 44.6 mmol) and methylurea (6.5 g, 89.3 mmol) in DMF (125 mL). Stir the reaction at 90° C. for 16 h under a nitrogen atmosphere. Cool to room temperature, dilute with hexane/EtOAc (1:1, 250 mL) and wash with 10% aqueous NaCl (4×75 mL). Collect the organic phase, concentrate in vacuo and purify the crude mixture by chromatography on silica gel (330 g) eluting with DCM/methanol (1:0 to 24:1 gradient) to obtain the desired intermediate (2.3 g, 26%). MS (ES+) m/z: 200.2 (M+H)+.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].C([O:11][C:12](=O)[CH2:13][C:14](=O)[C:15]([CH3:18])([CH3:17])[CH3:16])C>CO>[CH3:6][C:5]1[N:8]=[C:12]([OH:11])[CH:13]=[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nc(O)cc(C(C)(C)C)n1
Yield: 63.2 %

Procedure:
A suspension of 21.6 g (0.4 mol) of sodium methylate, 19.4 g (0.2 mol) of acetamidine hydrochloride, 34.4 g (0.2 mol) of pivaloylacetic acid ethyl ester and 100 ml of methanol was heated for 10 hours under reflux and then evaporated, and the residue was taken up in 350 ml of water. Concentrated hydrochloric acid was added to the aqueous solution, while cooling with ice, to a pH of about 6, and the mixture was then extracted twice with 200 ml of methylene chloride each time. The combined methylene chloride extracts were dried over sodium sulphate and then concentrated. 21 g (63% of theory) of 2-methyl-4-hydroxy-6-tert.-butyl-pyrimidine were obtained in the form of colorless crystals of melting point 131°-132° C.
Reaction SMILES: [N+:1]([C:4]1[C:14]([N+]([O-])=O)=[CH:13][C:12]2[CH:11]3[CH2:18][CH:7]([CH2:8][N:9]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:10]3)[C:6]=2[CH:5]=1)([O-:3])=[O:2].C([O-])(=[O:27])C.[K+]>CS(C)=O.O>[F:21][C:20]([F:23])([F:22])[C:19]([N:9]1[CH2:10][CH:11]2[CH2:18][CH:7]([C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:14]([OH:27])=[CH:13][C:12]=32)[CH2:8]1)=[O:24]
Reactant: CC(=O)[O-]
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12)C(F)(F)F
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c(O)cc12)C(F)(F)F
Temperature: 100 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7), 3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (900 mg, 2.61 mmol) and potassium acetate (KOAc) (2.6 g, 26.1 mmol) were dissolved in DMSO (10 mL) and warmed with stirring to 100° C. for 16 hours. The mixture was cooled and diluted with H2O (50 mL) then extracted with 80% EtOAc/hexanes (6×25 mL). The organic layer was washed with H2O (3×20 mL), dried (Na2SO4), filtered and concentrated and purified by chromatography to give an oil (575 mg, 70%). (TLC 50% EtOAc/hexanes (NH3) Rf 0.56)