Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:36][S:37]([CH2:40][CH2:41][NH2:42])(=[O:39])=[O:38]>>[F:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[CH2:28][O:27][C:26]1[CH:25]=[CH:24][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([CH2:22][NH:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:19][CH:18]=4)[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CS(=O)(=O)CCN
Reactant: COc1cc(Nc2ncnc3ccc(-c4ccc(C=O)o4)cc23)ccc1OCc1cccc(F)c1
Product: COc1cc(Nc2ncnc3ccc(-c4ccc(CNCCS(C)(=O)=O)o4)cc23)ccc1OCc1cccc(F)c1

Procedure:
Prepared according to Procedure D from 5-(4-{3-methoxy-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz (DMSO-d6) 9.22 (s, 1H); 8.78 (s, 1H); 8.31 (d, 1H); 7.88 (d, 1H); 7.50-7.08 (m, 8H); 6.84 (d, 1H); 5.13 (s, 2H); 4.42 (s, 2H); 3.80 (s, 3H); 3.60 (m, 2H); 3.40 (m, 2H, obscured by water peak); 3.10 (s, 3H); MS m/z 577 (M+1).
Reaction SMILES: ClC(Cl)C.[Cl:5][C:6]1[C:7]([F:34])=[C:8]([F:33])[CH:9]=[C:10]2[C:15]=1[N:14]([C:16]1[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([F:25])=[CH:18][C:17]=1[F:26])[CH:13]=[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:11]2=[O:32].[C:35](OC(=O)C)(=[O:37])C>[Pd].C(O)=O>[Cl:5][C:6]1[C:7]([F:34])=[C:8]([F:33])[CH:9]=[C:10]2[C:15]=1[N:14]([C:16]1[CH:21]=[C:20]([NH:22][CH:35]=[O:37])[C:19]([F:25])=[CH:18][C:17]=1[F:26])[CH:13]=[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:11]2=[O:32]
Reactant: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(Cl)Cl
Solvent: O=CO
Product: CCOC(=O)c1cn(-c2cc(NC=O)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 20 ml of dichloroethane and 10 ml of formic acid were added 2 g of ethyl 8-chloro-6,7-difluoro-1-(2,4-difluoro-5-nitrophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate and 200 mg of 10% palladium on carbon. Under a hydrogen atmosphere, the solution was stirred at room temperature for 3 hours and after addition of acetic anhydride, further stirred overnight. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. Diethyl ether was added to the residue whereupon the solid was collected by filtration and washed with ethanol and diethyl ether to give 1.9 g of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Br-].[CH2:31]([Zn+])[CH2:32][CH3:33]>C1(P([Pd](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:24]=[N:25][C:26]([CH2:31][CH2:32][CH3:33])=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCC[Zn+]
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(Cl)nc3)c2C#N)CC1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1ccc(Nc2ncnc(OC3CCN(C(=O)OC(C)C)CC3)c2C#N)cn1

Procedure:
In a 25 mL round-bottomed flask fitted with a condenser and N2 inlet was placed 4-[6-(6-chloro-pyridin-3-ylamino)-5-cyano-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (100 mg, 1.3 mmol), n-propylzinc bromide (0.5M in THF, 0.72 mL), tetrakis (triphenylphosphino)palladium (28 mg, 0.024 mmol), and THF (3.5 mL). The reaction mixture was refluxed overnight under N2 atmosphere. The product was purified by preparative HPLC. 1H NMR (CDCl3, 400 MHz) δ 1.03 (t, 3H), 1.26 (d, 6H), 1.85 (m, 4H), 1.98 (m, 2H), 3.04 (t, 2H), 3.44 (m, 2H), 3.77 (m, 2H), 4.94 (m, 1H), 5.46 (m, 1H), 7.57 (d, 1H), 8.34 (s, 1H), 8.51 (s, 1H), 8.56 (d, 1H), 9.42 (s, 1H). Exact mass calculated for C22H28N6O3 424.22, found 425.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:20]([N:22]([CH2:36][CH3:37])[C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH3:21]>>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:23]([N:22]([CH2:36][CH3:37])[CH2:20][CH3:21])=[O:35])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C:3]1=[O:12]
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 30 from 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 4-(N',N'-diethylureido)benzenesulfonyl chloride. M.p.=195°-196° C.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:41])[C@@H:17]([O:19][C:20]1[CH:40]=[CH:39][C:23]([CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=3)[C:27]([CH3:37])=[C:26]2[CH3:38])=[CH:22][CH:21]=1)[CH3:18]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:34]([C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[N:25]([CH2:24][C:23]2[CH:39]=[CH:40][C:20]([O:19][C@@H:17]([CH3:18])[C:16]([O:15][CH3:14])=[O:41])=[CH:21][CH:22]=2)[C:26]([CH3:38])=[C:27]3[CH3:37])=[O:35])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]([OH:15])=[O:14].[CH2:32]([O:39][C:40](N1C(=O)CCC1=O)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([O:39][C:40]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]([OH:15])=[O:14])=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 8 h

Procedure:
9.25 ml (53.09 mol) of N,N-diisopropylethylamine are added to a solution of 10.46 g (24.13 mmol) of 2(S)-amino-3-(2-benzyloxy-5-iodophenyl)propionic acid hydrochloride (Example 9A) in DMF. 6.615 g (26.54 mmol) of N-(benzyloxycarbonyl)succinimide (Z-OSuc) are added thereto. The resulting solution is stirred overnight and then concentrated on a rotary evaporator in vacuo. The residue is taken up in dichloromethane and extracted twice each with a 0.1N hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organic phase is dried, filtered and concentrated. The mixture is purified by column chromatography on silica gel (mobile phase: cyclohexane/diethyl ether 9:1 to 8:2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].[Br:19]Br>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([Br:19])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2n1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ncc2[nH]c3ccc(Br)cc3c2n1
Reaction time: 6 h

Procedure:
A solution is prepared from 1.15 g of 5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 3) in 50 ml of chloroform and 5.3 ml of pyridine and combined dropwise with 1 g (0.33 ml) of bromine in 10 ml of chloroform at room temperature. After 6 hours of agitation, the mixture is concentrated, taken up in 30 ml of water, made alkaline with ammonia, layered over with ethyl acetate, and then shaken and suctioned off. The thus-obtained residue is 0.86 g of 8-bromo-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester, mp 286°-290° C. (under decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[C:15]([Cl:21])[CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:7]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:9])=[C:15]([Cl:21])[CH:14]=1
Reactant: COc1ccc(C(=O)O)cn1
Reactant: Clc1cc(Br)ccc1CBr
Product: COc1ccc(C(=O)Cc2ccc(Br)cc2Cl)cn1

Procedure:
In analogy to Example 203, step 1, 6-methoxynicotinic acid was converted to the acid chloride and subsequently reacted with 4-bromo-1-bromomethyl-2-chloro-benzene to give the title compound (not completely pure) as a light yellow solid.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][C:9]([CH3:38])([CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:28]=[N:27][C:26]([C:29]3[NH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][N:33]=3)=[CH:25][N:24]=2)=[CH:18][N:17]=1)[C:10]([O:12][CH3:13])=[O:11].[CH3:39][Si:40]([CH3:47])([CH3:46])[CH2:41][CH2:42][O:43][CH2:44]Cl>O>[CH3:8][C:9]([CH3:38])([CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:28]=[N:27][C:26]([C:29]3[N:33]([CH2:44][O:43][CH2:42][CH2:41][Si:40]([CH3:47])([CH3:46])[CH3:39])[CH:32]=[C:31]([C:34]([F:35])([F:37])[F:36])[N:30]=3)=[CH:25][N:24]=2)=[CH:18][N:17]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(C)(C)COc1cc(C)c(-c2cnc(-c3ncc(C(F)(F)F)[nH]3)cn2)cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2cnc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60%, 35 mg) was added to an N,N-dimethylformamide (3 mL) solution containing methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoate (320 mg) at 0° C., and the resulting mixture was stirred at the same temperature for 1 hour. To the mixture was added 2-(trimethylsilyl)ethoxymethyl chloride (195 μL), a temperature of the mixture was raised to room temperature and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and then with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 80:20) to obtain a mixture (324 mg) of methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridin-2-yl)oxy]propanoate and methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-pyrazin-2-yl}pyridin-2-yl)oxy]propanoate.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:11]=3[CH:10]=2)=[CH:3][CH:2]=1.CO[C:23]([CH2:29][CH3:30])=[CH:24][C:25]([O:27][CH3:28])=[O:26].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:28][O:27][C:25](=[O:26])[CH2:24][C:23]1([CH2:29][CH3:30])[C:16]2[NH:15][C:12]3[C:11]([C:17]=2[CH2:18][CH2:19][O:20]1)=[CH:10][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[CH:14][CH:13]=3
Reactant: OCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CCC(=CC(=O)OC)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCC1(CC(=O)OC)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
A mixture consisting of 5-benzyloxytryptophol (24.0 g, 0.090 mol), methylene chloride (600 mL), methyl 3-methoxy-2-pentenoate (16.8 g, 0.177 mol) and borontrifluoride etherate (2 mL) is stirred at room temperature for 3 hours. The reaction mixture is washed with 5% NaHCO3 (2×200 mL), water (2×200 mL) and once with brine (200 mL), dried (MgSO4), filtered and concentrated to give 38.0 g crude product. The crude product is flash chromatographed on silica gel using 20% ethyl acetate/hexane as an eluent to afford 29.0 g pure title compound, m.p. 98°-100° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH:29]=[CH:28]1.CCCCCC>C1(C)C(C)=CC=CC=1>[CH2:16]([N:8]1[C:9](=[O:15])[C@H:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[N:5]([C:3](=[O:4])[CH2:2][NH:1][C:27](/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31])=[O:33])[C:6]2[CH:26]=[CH:25][CH:24]=[CH:23][C:7]1=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1C=CC(=O)O1
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: O=C(O)/C=C\C(=O)NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of (3aR*,10aS*)-4-(aminoacetyl)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta [e][1,4]diazepin-10(1H)-one (420 mg, 1.2 mmol) and maleic anhydride (118 mg, 1.2 mmol) was stirred for 30 minutes in xylene at 140° C. The reaction mixture was left standing for cooling at room temperature, to which was added hexane (5 mL). The resulting solid was collected by filtration, which was recrystallized from chloroform-ethanol-diethyl ether to give 420 mg (yield 78%) of the titled compound, m.p. 207°-209° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[C:12]([C:14]#[N:15])[N:13]=1.[OH-:25].[K+]>O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[O:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[C:12]([C:14]([NH2:15])=[O:25])[N:13]=1
Reactant: [OH-]
Reactant: COc1ccccc1Nc1oc(-c2c(F)cccc2F)nc1C#N
Agent: [K+]
Solvent: O
Product: COc1ccccc1Nc1oc(-c2c(F)cccc2F)nc1C(N)=O
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a suspension of 2-(2,6-difluorophenyl)-5-(2-methoxyphenylamino)oxazole-4-carbonitrile (0.018 g, 0.055 mmol, prepared according to the procedure described for Q-1 step a) in water (4.5 mL) was added 1M aqueous potassium hydroxide (0.27 mL, 0.27 mmol) and the resulting mixture stirred at 140° C. in the microwave for 15 minutes. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(2-methoxyphenylamino)oxazole-4-carboxamide (0.0104 g, 0.030 mmol, 55%). 1H NMR (DMSO) δ 3.92 (3H, s), 6.99 (1H, ddd), 7.04 (1H, ddd), 7.12 (1H, dd), 7.35 (2H, t), 7.42 (2H, br. s), 7.64 (1H, m), 7.68 (1H, dd), 9.48 (1H, s). LCMS (2) Rt: 2.86 min; m/z (ES+) 346.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[C:10]1(B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=2)[CH:3]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: Nc1ccc(Br)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ccc(Br)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 86.9 %

Procedure:
To a mixture of 4-bromo-2-iodo-phenylamine (2.00 g, 6.71 mmol), 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.40 g, 6.71 mmol) and Pd(PPh3)4 (388 mg, 0.336 mmol) in 40 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (26.8 mL, 53.7 mmol). After stirring at 80° C. for 5 h under Ar, the reaction was cooled to RT. The mixture was treated with EtOAc (100 mL), washed with H2O (3×30 mL) and brine (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (10-20% EtOAc/hexane) to give 1.47 g (87%) of the title compound as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C12H14BrN, 252.0 (M+H). found 252.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[N:26]#[C:27][NH2:28]>O1CCOCC1.Cl>[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)[C:27]([NH2:28])=[NH:26]
Reactant: N#CN
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 71 from (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone and cyanamide in dioxane/hydrogen chloride.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:17]=[N:16]2)[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].Br[C:30]1[C:31]([CH3:36])=[N:32][NH:33][C:34]=1[CH3:35].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:30]3[C:31]([CH3:36])=[N:32][NH:33][C:34]=3[CH3:35])[CH:17]=[N:16]2)[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1)#[N:2]
Reactant: Cc1n[nH]c(C)c1Br
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1n[nH]c(C)c1-c1cnn(C2(CC#N)CN(C(=O)OC(C)(C)C)C2)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
A mixture of tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (381 mg, 0.981 mmol, from Example 1, step 2), 4-bromo-3,5-dimethyl-1H-pyrazole (206 mg, 1.18 mmol), tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.098 mmol) and sodium carbonate (310 mg, 2.9 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was purged with N2 and stirred at 110° C. for 2 h. The reaction mixture was filtered, diluted with EtOAc, then washed with water. The organic layer was concentrated and purified on silica gel (eluting with 0-100% EtOAc/hexanes followed by 0-10% MeOH/dichloromethane) to give tert-butyl 3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidine-1-carboxylate (90 mg, 26%). LCMS calculated for C18H25N6O2 (M+H)+: m/z=357.2. Found: 357.2. This intermediate was treated with 4.0 M hydrogen chloride in dioxane (1.2 mL, 4.9 mmol) in methylene chloride (1 mL) at rt for 2 h. The mixture was stripped to dryness to give the desired product. LCMS calculated for C13H17N6 (M+H)+: m/z=257.1. Found: 257.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](SC)=[N:7][C:6]=2[CH:17]=1.O.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)=[N:7][C:6]=2[CH:17]=1
Reactant: CSC1=Nc2cc(O)ccc2Nc2cscc21
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2c(c1)N=C(N1CCN(c3ccccc3)CC1)c1cscc1N2

Procedure:
A solution of 7-hydroxy-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess N-phenylpiperazine and glacial acetic acid is heated at 140°-160° C. for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:25].O>CS(C)=O>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:25])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1NC1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 19 h
Yield: 16 %

Procedure:
4-Amino-1-benzylpiperidine (0.20 ml) was dissolved in dimethyl sulfoxide (0.2 ml), added with 2-chloro-3-nitrotoluene (0.13 ml) and stirred at 100° C. for 19 hours. The reaction mixture was added with water (2 ml) and extracted twice with ethyl acetate (2 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=3:1) to obtain 51.1 mg of the title compound. Yield: 16%.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][N:6]=[C:5]([CH2:8][OH:9])[CH2:4]1.[H-].[Na+].[CH3:12]I>C1COCC1>[CH3:12][O:9][CH2:8][C:5]1[CH:4]2[CH:3]([CH2:2]2)[O:7][N:6]=1
Reactant: CI
Reactant: OCC1=NOC(CCl)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1=NOC2CC12
Reaction time: 0.25 h

Procedure:
To a solution of (5-(chloromethyl)-4,5-dihydroisoxazol-3-yl)methanol (6c rac, 2.2 g, 14.71 mmol) in THF (40 mL) was added sodium hydride (60% dispersion in mineral oil, 0.372 ml, 17.65 mmol). The resulting mixture was stirred for 15 min followed by dropwise addition of methyl iodide (1.005 ml, 16.18 mmol). After 15 min, the reaction mixture was carefully quenched with aqueous saturated ammoniumchloride solution and diluted with water. The phases were separated and the aqueous phase was extracted with Et2O. The combined organic layers were dried over Na2SO4 and the filtrate was concentrated under reduced pressure to afford the title compound as a pale yellow oil. The oil was dissolved in THF (20 mL) and the solution was cooled 0° C. A solution of potassium tert-butoxide (1M in THF, 17.65 ml, 17.65 mmol) was added dropwise and the reaction mixture was stirred for 30 min at 0° C. The mixture was quenched with aqueous saturated ammoniumchloride solution, the phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the filtrate was concentrated under reduced pressure to afford the title compound as an orange oil as MS m/z=128.1[M+H]+. Calculated for C6H9NO2: 127.06.