Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:7]=[C:6]([C:21]([O:23]CC)=[O:22])[C:5]2=[O:26].Cl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:26]
Reactant: CCOC(=O)c1cn(-c2ccc(OC)cc2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)cc32)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To ethyl 6,7-difluoro-1-(4 -methoxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.61 g) are added 90% acetic acid (8.0 ml) and conc. hydrochloric acid (2.0 ml), and the mixture is heated with stirring at 110° C. for 2 hours. After the reaction, the solvent is distilled off under reduced pressure. The resulting residue is washed well with water to give 6,7-difluoro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.54 g) as colorless needles, m.p. 256°-258° C.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([C:25]([F:28])([F:27])[F:26])[CH2:19][C:20]([O:22]CC)=[O:21])=[C:8]2[CH3:29])=[CH:4][CH:3]=1.[OH-].[Na+].CCOCC.CCCCCC>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([C:25]([F:28])([F:26])[F:27])[CH2:19][C:20]([OH:22])=[O:21])=[C:8]2[CH3:29])=[CH:30][CH:31]=1
Reactant: CCOC(=O)CC(c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc2c(c1)c(C(CC(=O)O)C(F)(F)F)c(C)n2Cc1ccc(Br)cc1
Yield: 92.5 %

Procedure:
To a mixture of the ester from Step 4 (4.6 g, 9.2 mmol) in 45 mL of EtOH was added 10N NaOH (2.3 mL, 23 mmol) and the mixture was heated to reflux for 2 h. The mixture was cooled and concentrated and the residue was partitioned between ether and 1M HCl. The organic layer was dried over MgSO4 and evaporated to give a white solid. This material was swished with 10% ether/hexane to give 4.0 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[C:15]([F:21])[CH:14]=3)[C:11]([CH3:23])(O)[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:24].BrC1C=CC(C2C(C3C=CC(SC)=C(F)C=3)C(C)(O)ON=2)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[C:15]([F:21])[CH:14]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: CSc1ccc(C2C(c3ccc(Br)c(C)c3)=NOC2(C)O)cc1F
Agent: CSc1ccc(C2C(c3ccc(Br)cc3)=NOC2(C)O)cc1F
Product: CSc1ccc(-c2c(-c3ccc(Br)c(C)c3)noc2C)cc1F

Procedure:
The title compound was prepared according to the procedure of step 2 in the Example 168 using 3-(4-bromo-3-methylphenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol, instead of 3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13]([CH2:19][Cl:20])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:33].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13]([CH2:19][Cl:20])=[N:12][C:7]=3[C:8]([NH2:33])=[N:9][C:10]=2[CH:11]=1
Reactant: CC(C)Cn1c(CCl)nc2cnc3cc(Br)ccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)Cn1c(CCl)nc2c(N)nc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-bromo-2-(chloromethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (13.9 g, 39.4 mmol) in chloroform (300 mL) at room temperature was added mCPBA (77% pure, 17.7 g, 78.8 mmol) over ten minutes. The reaction mixture was stirred at room temperature for 3 hours, then concentrated ammonium hydroxide (150 mL) was added, followed by p-toluenesulfonyl chloride (9.00 g, 47.3 mmol, added in portions over 10 minutes). The mixture was stirred at room temperature for 1 hour, then was transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The organic layers were combined, dried over magnesium sulfate, filtered through CELITE filter agent, and concentrated under reduced pressure. The crude product was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with ethyl acetate in hexanes) to yield 7.69 g of 7-bromo-2-(chloromethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:10][C:11]1[CH:12]=[C:13]([CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:14]=[C:15]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][CH:22]([CH:24]1CCCC[CH2:25]1)C)[CH2:16]2.C(=O)([O-])[O-].[K+].[K+].CC(C)([O-])C.[Na+]>O.C(#N)C>[CH:22]1([CH2:21][N:17]2[CH2:16][C:15]3[C:19](=[C:11]([CH3:10])[CH:12]=[C:13]([CH2:30][CH:31]4[CH2:32][CH2:33][N:34]([CH2:4][C:3]5[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=5[F:1])[CH2:35][CH2:36]4)[CH:14]=3)[C:18]2=[O:20])[CH2:25][CH2:24]1
Reactant: Fc1ccccc1CBr
Reactant: Cc1cc(CC2CCNCC2)cc2c1C(=O)N(CC(C)C1CCCCC1)C2
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(CC2CCN(Cc3ccccc3F)CC2)cc2c1C(=O)N(CC1CC1)C2
Temperature: 80 °C
Reaction time: 4 h
Yield: 6.5 %

Procedure:
To a mixture of 2-Fluorobenzyl bromide (47 μL, 0.377 mmol), 7-methyl-5-piperidin-4-ylmethyl-2-cyclohexylpropyl-2,3-dihydro-isoindol-1-one (75 mg, 0.251 mmol) and potassium carbonate (104 mg, 0.753 mmol) was added acetonitrile (3.0 mL). The mixture was stirred at 80° C. for 4 hours. 1 scoop of Sodium tert-butoxide (˜200 mg) was added and stirring continued overnight at 80° C. The mixture was cooled to room temperature, water (2.0 mL) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Column chromatography provided the title compound as a yellow oil (6.6 mg, 6%). 1H NMR (300 MHz, CDCl3): δ 7.38 (m, 1H), 7.23-7.13 (m, 1H), 7.11-7.00 (m, 3H), 6.96 (s, 1H), 4.41 (s, 2H), 3.61 (s, 2H), 3.46-3.44 (d, 2H), 2.95-2.92 (d, 2H), 2.70 (s, 3H), 2.59-2.57 (d, 2H), 2.01-1.98 (t, 2H), 1.65-1.61 (m, 3H), 1.38-1.27 (m, 2H), 1.04 (m, 1H), 0.60-0.55 (m, 2H), 0.36-0.32 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[S:25][C:26]([CH2:30][CH3:31])=[C:27]([CH3:29])[N:28]=1>C(O)C>[CH2:30]([C:26]1[S:25][C:24]([NH:23][C:3]([C:5]2[N:6]([CH3:22])[S:7](=[O:20])(=[O:21])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:2])=[N:28][C:27]=1[CH3:29])[CH3:31]
Reactant: CCc1sc(N)nc1C
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: CCO
Product: CCc1sc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)nc1C
Yield: 63 %

Procedure:
N-(5-Ethyl-4-methyl-2-thiazolyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 22 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-5-ethyl-4-methyl-thiazole. Yield: 63% of theory; m.p. 253°-255° C (decomp.; from ethanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1>>[Cl:20][C:21]1[N:22]=[C:23]([NH2:28])[N:24]=[C:25]([NH:19][C:4]2[CH:3]=[C:2]([F:1])[C:7]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[NH:15][CH:16]=[CH:17][C:10]=34)=[C:6]([F:18])[CH:5]=2)[CH:26]=1
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Product: Nc1nc(Cl)cc(Nc2cc(F)c(Oc3ccnc4[nH]ccc34)c(F)c2)n1

Procedure:
Analogously to example 8, the title compound is synthesized from 384 mg (1.47 mmol) of [3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amine (from example XXXIV) and 241 mg (1.47 mmol) of 4,6-dichloro-2-pyrimidineamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH2:20][CH2:19][CH2:18][C:17](=[O:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][CH:7]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2)CCCC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1
Yield: 31.7 %

Procedure:
A solution of the 9-[(3-fluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (434.0 mg, 1.23 mM) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (324.0 mg, 1.42 mM) in 20 mL of toluene was stirred between 70-80° C. for 5 h. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride) to afford 137.0 mg (32%) of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole as a yellow foam. 1H NMR (DMSO-d6) δ 10.2 (s, 1H), 7.7 (d, 1H, J=8 Hz), 7.4 (t, 1H, J=8 Hz), 7.3 (m, 2H), 7.2 (d, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 7.05-6.85 (m, 3H), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), and 3.85 (s, 3H). IR (CHCl3, cm−1) 3200 (br), 1687, 1597, 1452, 1442, 1285, and 1267. MS (ES) m/e 348, 350.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13]1.[CH3:36][NH2:37]>O.O1CCOCC1>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:12]4([C:6]5[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:37][CH3:36])[CH2:14][CH2:13]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3cc(F)ccc3OCCCl)CC2)c1=O
Reactant: CN
Solvent: O
Solvent: C1COCCO1
Product: CNCCOc1ccc(F)cc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CC1

Procedure:
3-[3-[[1-[2-(2-chloroethoxy)-5-fluorophenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 278e, 0.25 g) and 40% methylamine in water (1 mL) were stirred together at 100° C. in dioxane (8 mL) in a sealed tube for 24 h. Purification of the cooled solution by preparative HPLC (Xbridge column—acetonitrile/0.2% ammonia mobile phase) gave the title compound (110 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=O)[O:19]C3C=CC([N+]([O-])=O)=CC=3)[C:12]([C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:32][CH:31]=3)=[CH:11][S:10]2)=[CH:4][CH:3]=1.[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45][NH2:46].[OH-].[Na+]>ClCCl>[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45][NH:46][C:18]([NH:17][CH2:16][CH2:15][CH2:14][N:13]1[C:12]([C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[CH:11][S:10][C:9]1=[N:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:19]
Reactant: O=C(NCCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)CCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(C)CCNC(=O)NCCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1
Reaction time: 1 h
Yield: 85.3 %

Procedure:
The compound (108 mg) obtained in Example 348 was dissolved in dichloromethane (3 ml), and thereto was added N,N-dimethyl-ethylenediamine (33 mg) at room temperature under nitrogen atmosphere, and the mixture was stirred for one hour. To the reaction mixture was added 1% aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (84 mg) as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([N:15]=CN(C)C)=[N:4][C:5](=[O:14])[N:6]([CH:8]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]2)[CH:7]=1.[CH:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>C(Cl)Cl.CN(C)C=O>[NH2:15][C:3]1[C:2]([F:1])=[CH:7][N:6]([CH:8]2[CH2:12][CH2:11][CH:10]([O:13][C:33](=[O:34])[NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:23]4[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=4)=[CH:31][CH:30]=3)[CH2:9]2)[C:5](=[O:14])[N:4]=1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Reactant: CN(C)C=Nc1nc(=O)n(C2CCC(O)C2)cc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nc(=O)n(C2CCC(OC(=O)Nc3ccc(-c4ccccc4)cc3)C2)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.2 %

Procedure:
A solution of N′-[5-fluoro-1-(3-hydroxy-cyclopentyl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine (0.050 g, 0.186 mmol) in CH2Cl2 (2 mL) and anhydrous dimethylformamide (1 mL) was treated with 4-biphenyl isocyanate (0.039 g, 0.2 mmol). The mixture was stirred at room temperature under nitrogen for 5 hours, then quenched by the addition of acetic acid (0.5 mL) and stirred 10 minutes. The mixture was concentrated in vacuo, loaded on silica gel, and chromatographed on silica gel (10 g SiO2, 8:1 ethyl acetate/methanol) to afford biphenyl-4-yl-carbamic acid 3-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-cyclopentyl ester 31 as a white solid (0.029 g, 38%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4](SC2C=CC=CC=2)[N:3]=1.[OH-:29].[Na+]>C(O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:29])[C:5]([C:20]#[N:21])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: [OH-]
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(N)[nH]c(=O)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
500 mg (1.29 mmol) of the compound from Example 99A are initially charged in 6.4 ml of ethanol. After addition of 2.57 g (28.96 mmol) of sodium hydroxide, the mixture is stirred at 80° C. for 30 min, and a clear solution is formed. After cooling to RT, the solvent is removed on a rotary evaporator. The residue is taken up in 3 ml of water and acidified with 1 N hydrochloric acid until a yellowish precipitate is formed. The suspension is stirred at RT for 3 h. The precipitate is filtered off, washed with about 5 ml of water and a little ethanol and then recrystallized from about 10 ml of ethanol. The product obtained in this manner is used without further purification in the subsequent reactions.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]([CH3:35])([CH3:34])[S:30][CH2:29]1.CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[C:32](=[O:33])[C:31]([CH3:34])([CH3:35])[S:30][CH2:29]4)[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)SCN(CCCCBr)C1=O
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)SCN(CCCCN2CCN(c3n[nH]c4cc(F)ccc34)CC2)C1=O
Yield: 34.6 %

Procedure:
To a stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole (4.4 g), K2CO3 (2.8 g), 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (6.6 g) and dimethylformamide (75 ml) was heated at 75° for 4 hours. The reaction was poured into H2O, and the aqueous mixture extracted with ethyl acetate. The ethyl acetate was washed (H2O), dried (MgSO4) and the solvent concentrated to afford an oil. Upon standing the oil crystallized, and when the mass was triturated with ether, 3.3 g of a solid was collected. The compound was recrystallized from toluene-hexane to yield 2.8 g of 3-(4-(1-[6-fluoro-1H-indazol-3-yl]-4-piperazinyl)-butyl)-5,5-dimethyl-4-thiazolidinone, m.p. 123°-125° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:25]=1[C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Clc1cc(-c2ccc3ccccc3c2)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: c1ccc2cc(-c3cc(-c4ccc5ccccc5c4)ncn3)ccc2c1
Yield: 19 %

Procedure:
Next, into a recovery flask equipped with a reflux pipe were put 3.9 g of 4-chloro-6-(naphthalen-2-yl)pyrimidine obtained in Step 1, 2.8 g of 2-naphthaleneboronic acid, 1.7 g of sodium carbonate, 0.14 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, into the flask were further put 1.4 g of 2-naphthaleneboronic acid, 0.9 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by flash column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 5:1, so that a pyrimidine derivative Hd2npm, which was the objective substance, was obtained (yellow white powder, yield of 19%). A synthesis scheme (h-2) of Step 2 is shown below.
Reaction SMILES: [NH:1]1[C:8]2[N:4]([N:5]=[CH:6][CH:7]=2)[CH:3]=[CH:2]1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>O1CCCC1>[C:9]([N:1]1[C:8]2[N:4]([N:5]=[CH:6][CH:7]=2)[CH:3]=[CH:2]1)(=[O:11])[CH3:10]
Reactant: c1cc2[nH]ccn2n1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)n1ccn2nccc12
Temperature: 35 °C

Procedure:
To a solution of 1H-imidazo[1,2-b]pyrazole (2.5 g) in tetrahydrofuran (10 ml) was added acetic anhydride (3.1 ml) under stirring at 35° C. and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was evaporated in vacuo to give 1-acetyl-1H-imidazo[1,2-b]-pyrazole (2.7 g).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH:18]=[C:19](Cl)[CH:20]=[CH:21][C:16]=2[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:30]([NH:37][C@H:38]([CH2:43][OH:44])[CH2:39][CH:40]([CH3:42])[CH3:41])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[C:17]2[CH:18]=[C:19]([O:44][CH2:43][C@@H:38]([NH:37][C:30](=[O:31])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH:20]=[CH:21][C:16]=2[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2cnccc2c2ccc(Cl)cc2n1Cc1ccccc1
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(Cc3ccccc3)c2c1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a solution 6-benzyl-8-chlorobenzo[c][2,7]naphthyridin-5(6H)-one (640 mg, 2.00 mmol) in toluene (12 mL) at room temperature, was added cesium carbonate (975 mg, 2.99 mmol) and N-Boc L-Leucinol (1287 mg, 5.99 mmol) and the mixture was degassed with nitrogen for 5 min. The mixture was then treated with di-tert-butyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (508 mg, 1.197 mmol) followed by palladium(II)acetate (448 mg, 2.00 mmol) and degassed for another 10 min. The reaction mixture was sealed and heated at 80° C. After overnight stirring the reaction mixture was cooled to room temperature and filtered through diatomaceous earth (Celite®). The bed was washed with ethyl acetate and the combined filtrate was concentrated under reduced pressure to afford crude product which was purified by combi flash (ethyl acetate/petroleum ether) to afford (S)-tert-butyl (1-((6-benzyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (500 mg, 0.738 mmol, 37% yield) as an off-white solid. LC/MS (ESI) m/e 502.3 [(M+H)+, calcd for C30H36N3O4 502.4]; LC/MS retention time (method D): tR=1.26 min.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Na].Br[C:7]1[N:14]=[C:13]([NH2:15])[CH:12]=[C:11]([NH2:16])[C:8]=1[C:9]#[N:10]>O>[NH2:16][C:11]1[C:8]([C:9]#[N:10])=[C:7]([O:3][CH2:2][CH2:1][OH:4])[N:14]=[C:13]([NH2:15])[CH:12]=1
Reactant: OCCO
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [Na]
Solvent: O
Product: N#Cc1c(N)cc(N)nc1OCCO
Temperature: 150 °C
Yield: 44 %

Procedure:
A heavy walled, sealable tube suitable for microwave heating was charged with 3 mL of ethylene glycol and 50 mg (2.2 mmol) of sodium. The mixture was stirred at 95° C. until all of the sodium had reacted, then 213 mg (1.00 mmol) of 2-bromo-4,6-diaminonicotinonitrile was added. The tube was sealed, and the mixture was heated with a microwave apparatus at 150° C. for 10 minutes then cooled. The mixture was diluted with 15 mL of water, and extracted with ethyl acetate (3×5 mL). The combined ethyl acetate layers were back extracted with water (1×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to provide 85 mg (44%) of a solid. 1H NMR (300 MHz, d6-DMSO) δ 6.20 (s, 2H), 6.16 (s, 2H), 5.32 (s, 1H), 4.76 (t, 1H, J=5.3 Hz), 4.21 (m, 2H), 3.64 (q, 2H, J=5.4 Hz); MS (ESI) m/e=151 (M−EtOH+H)+, 195 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.C(N(CC)CC)C.[Si]([O:44][CH2:45][CH:46]=O)(C(C)(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.O>CO.O1CCCC1.C(#N)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([CH2:46][CH2:45][OH:44])[CH2:6]4)[C:12]([F:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(CCO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (19 mg, 0.041 mmol, racemic intermediate from Example 67, Step 1) and triethylamine (28 μL, 0.20 mmol) in methanol (0.1 mL)/acetonitrile (0.1 mL)/tetrahydrofuran (0.1 mL) was added {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (39 μL, 0.20 mmol), followed by sodium triacetoxyborohydride (22 mg, 0.10 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was treated with 6.0 M hydrogen chloride in water (0.07 mL, 0.4 mmol) at room temperature for 10 min and then purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.5 mg, 13%). The product was isolated as a racemic mixture. LCMS calculated for C20H25ClFN6O2 (M+H)+: m/z=435.2; Found: 435.1.