Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:22]([CH2:23][CH2:24][CH2:25]Br)[C:21](=[O:27])[C:20]3[C:15](=[CH:16][C:17]([O:30][CH3:31])=[CH:18][C:19]=3[O:28][CH3:29])[N:14]=2)=[CH:8][C:7]=1[CH3:32].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.O>CN(C=O)C>[CH3:32][C:7]1[CH:8]=[C:9]([C:13]2[N:22]([CH2:23][CH2:24][CH2:25][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:21](=[O:27])[C:20]3[C:15](=[CH:16][C:17]([O:30][CH3:31])=[CH:18][C:19]=3[O:28][CH3:29])[N:14]=2)[CH:10]=[C:11]([CH3:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C1CCNC1
Reactant: COc1cc(OC)c2c(=O)n(CCCBr)c(-c3cc(C)c(OCCCBr)c(C)c3)nc2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)n(CCCN3CCCC3)c(-c3cc(C)c(OCCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(3-bromo-propoxy)-3,5-dimethyl-phenyl]-3-(3-bromo-propyl)-5,7-dimethoxy-3H-quinazolin-4-one (0.76 g, 1.35 mmol) in DMF (10 mL) were added pyrrolidine (0.77 g, 10.77 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, water was added and product was extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with water, then brine, and dried over Na2SO4. Solvent was evaporated to give the title compound as a white solid. Yield: 0.12 g (16%). MP 109-111° C. 1H NMR (400 MHz, CDCl3): δ 8.16 (s, 2H), 6.93 (d, J=2.4 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 4.71 (t, J=6.4 Hz, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.87 (t, J=6.0 Hz, 2H), 2.75 (m, 4H), 2.60 (m, 8H), 2.37 (s, 6H), 2.16 (m, 2H), 2.05 (m, 2H), 1.82 (m, 8H). MS (ES) m/z: 549.75 (M+1). Analysis calculated for C32H44N4O4.0.5H2O (FW 557.73), %: C, 68.91; H, 8.13; N, 10.05. Found, %: C, 68.71; H, 8.56; N, 9.74.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20](Cl)=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Reactant: COCCN
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(NCCOC)cccc23)n1
Yield: 93 %

Procedure:
A mixture of N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (56 mg, 0.14 mmol) and 2-methoxyethylamine (5 mL) was heated to reflux for 24 hours, then cooled and concentrated. Flash column chromatography eluting with 3:1 hexanes:ethyl acetate afforded 3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-α]pyridin-7-amine (57.1 mg, 93%) as a yellow foam. 1H NMR (CDCl3): δ 8.02 (d, 1H), 7.76 (d, 1H), 7.65 (m, 2H), 7.32 (t, 1H), 7.15 (t, 2H), 6.29 (m, 2H), 6.05 (d, 1H), 5.10 (broad, 1H), 3.72 (t, 2H), 3.57 (q, 2H), 3.47 (q, 2H), 3.43 (s, 3H), 1.69–1.44 (m, 4H), 0.98 (t, 3H); MS m/z 435 (M+1).
Reaction SMILES: C(OC([NH:11][C:12]([C@H:14]1[C@@H:17]([C:18]([NH2:20])=[O:19])[CH2:16][NH:15]1)=[O:13])=O)C1C=CC=CC=1.[H][H]>CO>[NH:15]1[CH2:16][C@H:17]([C:18]([NH2:20])=[O:19])[C@@H:14]1[C:12]([NH2:11])=[O:13]
Reactant: [H][H]
Reactant: NC(=O)[C@H]1CN[C@H]1C(=O)NC(=O)OCc1ccccc1
Solvent: CO
Product: NC(=O)[C@H]1CN[C@H]1C(N)=O

Procedure:
A solution of cis-N-(benzyloxycarbonyl)azetidine-2,3dicarboxylic acid and, e.g., ammonia are reacted with [(CH3)2N]3PCl2 to form the cis-N-(benzyloxycarbonyl)azetidine-2,3-dicarboxamide (XI), as set forth by Appel et al., Chem. Ber. 116, 2037-2040 (1983). XI, 10% pd/C and methanol are hydrogenated in a Parr shaker under 3 atm of hydrogen, for 4 hours. The catalyst is filtered off and thoroughly washed. The solution is evaporated to dryness and dried in vacuo to arrive at cis-azetidine-2,3-dicarboxamide.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:15]=[CH:16][CH:17]=[CH:18][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCNc3ncccc32)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 10 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (50 mg) was dissolved in anhydrous tetrahydrofuran and added to LiAlH4 (1 M in tetrahydrofuran, 9.0 eq) over 2 minutes. After stirring for 35 minutes at room temperature, the reaction mixture was quenched with wet ether, diluted with ethyl acetate and H2O, and filtered. The organic phase was isolated, dried, filtered, and concentrated. Silica gel chromatography (0-10% methanol in CH2Cl2) gave the title compound as a pale yellow film (10% yield). M.p. (film), LCMS: m/z=226.19 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.35-3.40 (m, 2H), 3.52-3.57 (m, 2H), 4.40 (s, 2H), 4.83 (bs, 1H), 6.41-6.50 (m, 1H), 6.56-6.63 (m, 1H), 7.20-7.38 (m, 5H), 7.43 (d, J=1.2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].CC([O-])(C)C.[K+].CS([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1)(=O)=O.O>C1COCC1>[CH3:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[N:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: N#Cc1ccc(O)cc1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(C#N)cc2)nc1

Procedure:
To 3.04 g of 4-cyanophenol dissolved in a 15 ml THF/15 ml DMSO mixture was added 2.86 g of t-BuOK and then 6 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture heated at 60° C. for 11/2 hrs. After cooling, the reaction mixture was poured into water and the solid which formed collected. Recrystallization from acetonitrile gave purified 4-((5-(methylsulfonyl)-2-pyridinyl)oxy)benzonitrile, m.p. 195°-196° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13](=[O:31])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42]O)=[CH:37][CH:36]=1)([O-:34])=[O:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:15]([NH:14][C:13]([C:3]1[CH:4]=[C:5]([O:12][CH2:42][CH2:41][C:38]2[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=2)[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1])=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCNC(=O)c1cc(O)c2ccccc2c1O
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNC(=O)c1cc(OCCc2ccc([N+](=O)[O-])cc2)c2ccccc2c1O
Yield: 48.9 %

Procedure:
A mixture composed of 42.7 g (0.1 mol) of 1,4-dihydroxy-2-(N-hexadecylcarbamoyl)naphthalene, 50.1 g (0.3 mol) of 2-(p-nitrophenyl)ethanol, 19 g of p-toluenesulfonic acid and 600 ml of toluene was refluxed by heating for 5 hours and the resulting water was removed by azeotropic distillation. After allowing to cool, toluene was distilled from the reaction mixture under a reduced pressure and the residue was dissolved in ethyl acetate. After washing with water, the thyl acetate was distilled off under a reduced pressure to concentrate and the residue was purified by a silica gel chromatography to obtain 28.2 g of 2-(N-hexadecylcarbamoyl)-4-[2-(p-nitrophenyl)ethoxy]-1-naphthol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[N:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:8]([C:6]1[CH:5]=[N:4][C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:2]([CH3:1])[N:7]=1)[CH3:9])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(C)n1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1nc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)(F)F
Yield: 68 %

Procedure:
The title compound is prepared in 68% yield (347 mg, a pale brown oil) from 1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanone (350 mg, 1.50 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (217 mg, 1.79 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][O:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][CH:26]=1>>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH2:8][C:2]2([NH:1][CH2:30][CH2:29][C:28]3[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: NC1(COC(c2ccccc2)c2ccccc2)CCCCC1
Product: COc1ccc(CCNC2(COC(c3ccccc3)c3ccccc3)CCCCC2)cc1

Procedure:
The title compound was prepared as described in Example 1 using 1-amino-1-diphenylmethoxymethylcyclohexane (see Preparation 3) and 4-methoxyphenethyl bromide. The title compound was obtained as a colourless oil (0.88 g, 68%) which was characterised from its 1H-n.m.r. spectrum.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:26])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:22]([CH3:23])=[N:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=2)=[CH:11][CH:10]=1)C>O>[CH3:23][C:22]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9](/[CH:8]=[CH:7]/[C:6]([OH:26])=[O:5])=[CH:10][CH:11]=2)=[N:18][C:19]([CH3:25])=[C:20]([CH3:24])[N:21]=1
Reactant: CCOC(=O)/C=C/c1ccc(OCc2nc(C)c(C)nc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(C)c(COc2ccc(/C=C/C(=O)O)cc2)nc1C
Yield: 93 %

Procedure:
Adding water (20 mL), NaOH (0.14 g, 3.5 mmol) into a 100 mL round-bottom flask, stirring to dissolve, then adding 95% alcohol (20 mL), (E)-3-(4-((3,5,6-Trimethylpyrazin-2-yl)methoxy)-phenyl)acrylic acid ethyl ester (1.0 g, 3.07 mmol), stifling under room temperature to react for 4 hours, TLC [V(petroleum ether):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.5, Rf of product=0), distilling out the alcohol under reduced pressure, adjusting pH of the reaction solution to 4-5 with 6.0M HCl while keeping the reaction solution cool to separate out solid, filtering, washing the solid with cool water for three times, processing with vacuum filtration, recrystallizing with anhydrous alcohol, drying under 70° C. for 8 hours to obtain 0.85 g white crystalloid of (E)-3-(4-((3,5,6-Trimethylpyrazin-2-yl)methoxy)-phenyl)acrylic acid, wherein a yield is 93.0%, m.p. 152-154° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].Cl.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:24]([C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=2)[N:25]=1)=[O:15]
Reactant: NNc1ccc(Br)cc1
Reactant: COC(=O)C(=O)C=Cc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1
Temperature: 125 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
4-(2-Chloro-phenyl)-2-oxo-3-butenoic acid methyl ester (4.9 g, 21.9 mmol) prepared in Step 2 and 4-bromophenylhydrazine hydrochloride (5.0 g, 22.4 mmol) was added to acetic acid (50.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting yellow liquid residue was crystallized from diethyl ether to give 5.3 g of the titled compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2].[C:39]([O-])([O-])=O.[K+].[K+]>CC(C)=O.CI>[C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:39])[C:19](=[O:24])[C:20]([F:21])([F:23])[F:22])[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1NC(=O)C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)c1ccccc1C1CCNc2c(C#N)c(-c3ccc(Oc4ccc(F)cc4)cc3)nn21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of N-(2-(3-cyano-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide (187 mg, 0.36 mmol) in acetone (10 mL) was added K2CO3 (100 mg, 0.72 mmol) and CH3I (15 drops). After stirring at RT for 2 hr, the mixture was filtered. The filtrate was concentrated to afford 192 mg (100%) of N-(2-(3-cyano-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoro-N-methylacetamide as yellow solid. MS (ESI) m/e [M+1]+ 535.8.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34]>CS(C)=O>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)CCNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1

Procedure:
A mixture of 10-[[6-chloro-3-pyridinyl]carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (3.2 g), K2CO3 (5 g) and the 2-dimethylamino-ethylamine (5 ml) is heated in dimethylsulfoxide (80 ml) for 6 hours at 100° C. (with stirring). The reaction mixture is quenched with water and the solid which separates, is filtered off and washed well with water. Examination of the TLC (CHCl3 :MeOH; 3:1) showed the products to be sufficiently pure to be used for further reactions without purification. Yield 3.2 g, 85%, mass spectrum (CI) 376 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:38]1([CH2:44][CH2:45][CH2:46]O)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C1COCC1>[N:13]1([C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([O:1][CH2:46][CH2:45][CH2:44][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:10][CH:9]=3)=[O:12])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: OCCCN1CCCCC1
Reactant: O=C(c1cc2cc(O)ccc2[nH]1)N1CCOCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1cc2cc(OCCCN3CCCCC3)ccc2[nH]1)N1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of 246 mg (1 mmol) (5-hydroxy-1H-indol-2-yl)-morpholin-4-yl-methanone, 1 g (ca. 3 mmol) polymerbound triphenylphospine (Fluka), 179 mg (1.25 mmol) piperidinepropanol and 461 mg (2 mmol) di-tert.-butyl azadicarboxylate in 20 ml THF was stirred for a prolonged period of time at room temperature. The mixture was filtered through a pad of silica and washed with 30 ml THF. The mixture was evaporated to dryness and purified on silica eluting with a gradient of DCM/2N NH3 in methanol 98/2 to DCM/2N NH3 in methanol 9/1. The product fractions were evaporated and the residue was titurated with diethyl ether to yield after drying at 40° C. under vacuum 47 mg (13%) of the title compound as white solid. MS (m/e): 372.4 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[ClH:28].[C:29]([C:33]1[N:38]=[C:37]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][CH2:48][NH:49][CH3:50])[CH2:41][CH2:40]2)[CH:36]=[C:35]([CH:51]2[CH2:54][CH2:53][CH2:52]2)[N:34]=1)([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[ClH:28].[C:29]([C:33]1[N:38]=[C:37]([N:39]2[CH2:40][CH2:41][N:42]([CH2:45][CH2:46][CH2:47][CH2:48][N:49]([CH3:50])[C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:43][CH2:44]2)[CH:36]=[C:35]([CH:51]2[CH2:54][CH2:53][CH2:52]2)[N:34]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CNCCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1)C(=O)c1ccc(F)cc1
Reaction time: 16 h
Yield: 41.8 %

Procedure:
0.5 g of 4-fluorobenzoic acid (3.57 mmol) and 1.27 g of triethylamine (12.57 mmol) were dissolved in 40 ml of dimethylformamide. 0.5 g of hydroxybenzotriazole (HOBt, 3.7 mmol), 1.3 g of {4-[4-(2-tert-Butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butyl}-methyl-amine hydrochloride (2.77 mmol), and 0.75 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 3.91 mmol) were added at room temperature, and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate, the organic phase dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2%). The residue was re-dissolved in isopropanol, treated with 4 N hydrochloric acid in dioxan. The precipitate was collected by filtration and dried to yield 0.6 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28](=[O:40])[C@@H:29]([N:31](C)[C:32](=O)OC(C)(C)C)[CH3:30])[CH2:22]3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28](=[O:40])[C@@H:29]([NH:31][CH3:32])[CH3:30])[CH2:22]3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C#C[C@@H]1CCC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#C[C@@H]1CCC[C@H](NC(=O)[C@H](C)NC)C1
Reaction time: 0.75 h
Yield: 29.2 %

Procedure:
To a solution of tert-butyl ((S)-1-((1S*,3R*)-(3-((2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)ethynyl)cyclohexyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (M6, 113 mg) in 1,4-dioxane (2 mL), a 4.0 mol/L solution of hydrochloric acid in 1,4-dioxane (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours and 45 minutes. The solvent was evaporated under reduced pressure, and to the obtained residue, ethyl acetate was added. The solid matter was taken by filtration, and then ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain (S)—N-((1S*,3R*)-3-((2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)ethynyl)cyclohexyl)-2-(methylamino)propanamide (M7, 27 mg).
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]([CH:7]([C:10]#[N:11])[C:8]#[N:9])([CH3:6])[CH3:5]>CCO>[CH:4]([C:7]1[C:10]([NH2:11])=[N:2][NH:3][C:8]=1[NH2:9])([CH3:6])[CH3:5]
Reactant: CC(C)C(C#N)C#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)c1c(N)n[nH]c1N
Temperature: 80 °C

Procedure:
Hydrazine monohydrate (2.05 mL, 42 mmol) was added to a solution of the product from Example 112A (1.16 g, 10.7 mmol) in EtOH (15 mL). The reaction flask was evacuated and purged with nitrogen (3 cycles), then heated at 80° C. for 22 hours. The yellow solution was cooled to room temperature and concentrated under vacuum. Toluene (8 mL) was added to the residue, and the mixture was concentrated under vacuum to remove excess hydrazine (repeated twice more) to provide the title compound. MS (ESI) m/z 141 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10](I)=[N:11][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:11][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Ic1n[nH]c2cccc(Oc3ccccc3)c12
Product: c1ccc(Oc2cccc3[nH]nc(-c4ccccc4)c23)cc1

Procedure:
In Scheme I, fluoronitrotoluene a is reacted with phenol b in the presence of mild base such as potassium carbonate, to afford a phenoxy nitrotoluene c. Phenoxy nitrotoluene c is then reduced, using catalyzed hyrdogenation or othe reduction technique, to provide phenoxy aminotoluene d. Phenoxy aminotoluene d undergoes a cyclization reaction by treatment with isoamyl nitrate to form phenoxy indazole e. Phenoxy indazole e is subject to iodine under basic conditions to yield a phenoxy iodoindazine f, which is then protected via Boc, Fmoc or other suitable protection scheme, to afford a protected phenoxy iodoindazole g. The protected phenoxy iodoindazole g is treated with a phenyl boronic acid h in the presence of a suitable catalyst to form a phenoxy phenylindazole i, which is deprotected to provide an indazole derivative j in accordance with the invention.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.Cl.[CH3:19]O>>[CH3:19][O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([NH2:2])=[CH:17][CH:16]=1
Reactant: Nc1ccc(OCCCCCC(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCCOc1ccc(N)cc1

Procedure:
To a mixture of 6-(4-Amino-phenoxy)-hexanoic acid Hydrochloride 66 (150 grams, 578 mmol), in methanol (3 liters) was passed dry HCl gas at 10° C. for 1 hour and refluxed for 48 hours. Methanol (1.5 liter) was distilled, ice water (1 liter) was added and the pH was adjusted to 7.5 with K2CO3. Crude 67 was extracted into chloroform, washed with 5% NaHCO3 solution, water, dried over Na2SO4 and distilled to give 67 (60 grams, 43.8) as a thick brown syrup. The structure was confirmed with NMR. IHNMR (CDCl3) δ 1.5 (m, 2H,CH2), 1.72(m, 4H, CH2), 2.34(t, 2H, CH2), 3.66(s,3H,ester), 3.85(t,2H,OCH2), 6.56(d,2H,Ar), 6.68(d,2H,Ar).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:17])[NH:14][C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:31][Si:32]([CH2:35][CH2:36][O:37][CH2:38]Cl)([CH3:34])[CH3:33]>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:17])[N:14]([CH2:38][O:37][CH2:36][CH2:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCCCc1ncc(/C=C2\NC(=O)NC2=O)n1Cc1ccc(C(=O)OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C2\NC(=O)N(COCC[Si](C)(C)C)C2=O)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 0.08 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[(2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (0.200 g, 0.524 mmol) in DMF (2 mL) is added sodium hydride (80% in oil, 0.02 g, 0.67 mmol) and the mixture stirred for 5 minutes. (Trimethylsilyl)ethoxymethyl chloride SEM-C1 (0.100 mL, 0.536 mmol) is added and the mixture allowed to stir for 16 hours. The solvents are removed in vacuo and the residue dissolved in ethyl acetate and water. After drying the organic fraction over MgSO4, the required product is isolated by chromatography, eluting with 0.5% methanol in chloroform. Crystallized from ether.