Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:24].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>C1COCC1>[CH3:25][N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=5)=[O:13])[CH:10]=4)[NH:5][C:4]3=[O:24])=[CH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(N4CCN(C)CC4)cc2)C(=O)N3)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 62.6 %

Procedure:
A small screw cap test tube was charged with N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (as prepared in Example 11, 50 mg, 0.155 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (32.6 mg, 0.170 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 62% (48 mg, 0.097 mmol) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C:18]([CH3:23])([CH3:22])[CH:19]([OH:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1.CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]([CH3:23])([CH3:22])[C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(O)C(C)(C)c1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)C(C)(C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a stirred solution of oxalyl chloride (3.4 mL, 40 mmol, 2 eq) in CH2Cl2 (100 mL) at −78° C. was added DMSO (4.9 mL, 70 mmol, 3.5 eq) dropwide. After stirring 1 h, the reaction mixture was treated dropwise with a solution of 3-(3-chlorophenyl)-3-methylbutan-2-ol (3.98 g, 20 mmol) in CH2Cl2 (100 mL). After stirring 1 h, Et3N (13.9 mL, 100 mmol, 5 eq) was added to the reaction mixture and the resulting mixture was slowly warmed to room temperature. The reaction mixture was partitioned in CH2Cl2 and water. The organic layer was separated, washed with 1N HCl and water, dried over MgSO4 and evaporated in vacuo to give 3-(3-chlorophenyl)-3-methylbutan-2-one (3.9 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.29 (m, 3H), 7.13 (m, 1H), 1.97 (s, 3H), 1.47 (s, 6H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>O>[CH2:9]([N:11]([CH2:12][CH3:13])[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)[CH3:10]
Reactant: CCNCC
Reactant: O=Cc1ccc(Br)s1
Solvent: O
Product: CCN(CC)c1ccc(C=O)s1
Yield: 54 %

Procedure:
In a round flask (100 mL) was added 5-bromothiophene-2-carboxaldehyde (1.37 mL) in 15 mL of distilled water. Diethylamine (12 mL) was added slowly, followed by refluxing for six days. Purification by flash chromatography provided the title compound as a brownish oil (1.13 g, 54%). 1H-NMR (300 MHz, [D] acetone): δ=9.46 (s, 1H), 7.56 (d, 1H, 3J=4.4 Hz), 6.07 (d, 1H, 3J=4.4 Hz), 3.485 (q, 4H, 3J=7.1 Hz), 1.23 (t, 6H, 3J=7.1 Hz). 13C-NMR (300 MHz, [D] acetone): δ=179.2, 166.0, 140.8, 125.9, 102.8, 47.6, 11.8.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][Si](C)(C)C)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[Li+].[OH-].Cl>CO.O>[CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(O[Si](C)(C)C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(O)ccc1C(=O)O
Temperature: 0 °C
Yield: 31.6 %

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 5.7 g methyl 2-methyl-4-trimethylsilyloxybenzoate and 2.0 g LiOH in 40 mL methanol and 10 mL water. After 2 hours at reflux the reaction was poured into 10 mL concentrated HCl and then 100 g ice. Extraction with ethyl acetate followed by concentration in vacuo gave a crude solid (70:30) product:starting material. Flash Chromatography using 50-50 ethyl acetate/hexanes as an eluent gave 1.15 g 2-methyl-4-hydroxybenzoic acid, m/e=193(M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][S:15][C:14]2[CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=[CH:21][C:13]1=2)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.NN>CO.[Ni]>[NH2:22][C:19]1[CH:20]=[CH:21][C:13]2[N:12]([CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:17][CH2:16][S:15][C:14]=2[CH:18]=1
Reactant: CN(CCN1CCSc2cc([N+](=O)[O-])ccc21)C(=O)OC(C)(C)C
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN(CCN1CCSc2cc(N)ccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a solution of tert-butyl methyl(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (0.8811 g, 2.493 mmol) in MeOH (20 mL) was added Raney-Nickel (slurry in water; 0.5 g, 2.493 mmol) followed by hydrazine hydrate (1.213 mL, 24.93 mmol). The mixture was then immersed in a preheated oil bath and refluxed for 5 minutes The solution was cooled to room temperature and filtered through a pad of Celite. The filter pad was washed with MeOH, and the crude material was concentrated. The crude material was then filtered through a silica plug (70% EtOAc/hexanes). The collected fractions were concentrated to give brown oil (0.78 g, 98%). 1H NMR (CDCl3) δ 6.64-6.58 (m, 1H), 6.45 (d, J=2.4 Hz, 1H), 6.39 (d, J=8.4 Hz, 1H), 3.53-3.50 (m, 2H), 3.39-3.28 (m, 4H), 3.01-2.98 (m, 2H), 2.90 (s, 3H), 1.45 (s, 9H); ESI-MS (m/z, %): 326, 324 (MH+, 95), 268 (100).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1.[BH4-].[Na+].[Na+].[Cl-]>C1(C)C=CC=CC=1.O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:30][CH2:29][CH2:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NCCc1ccc(Cl)cc1
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1ccc(C#Cc2ccc(CNCCc3ccc(Cl)cc3)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A solution of 4-[(4-butylphenyl)ethynyl]benzaldehyde (2.62 g, 10.0 mmol, intermediate to which may be obtained according to methods disclosed in EP03103780.7) and 2-(4-chlorophenyl)ethylamine (Aldrich, 1.56 g, 10 mmol) was heated at reflux in toluene (50 mL) for 12 hrs with azeotropic removal of water. The mixture was evaporated under vacuum and the residue was taken up in MeOH (60 mL) and chilled at 0° C. NaBH4(567 mg, 15.0 mmol) was added portionwise and the reaction mixture was stirred for 30 min at 0° C. and 3 hrs at rt. The reaction mixture was poured into a saturated solution of NaCl and extracted with Et2O. The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give the crude product. Purification by chromatography on silicagel (EtOAc/c-hex 30/70) gave 2.96 g (54%) of the title compound as a white solid. HPLC, Rt: 5.0 min (purity: 99.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:26])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH:16]2[C:22]([O:24][CH3:25])=[O:23])=[CH:5][CH:4]=1.[O:27]1[C:36]2[CH:35]=[C:34]([CH2:37][NH2:38])[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:27]1[C:36]2[CH:35]=[C:34]([CH2:37][NH:38][CH:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[N:7]=[CH:8][C:9]4=[O:26])[CH:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17]3)[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1
Reactant: COC(=O)C1CC(=O)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Reactant: NCc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)C1CC(NCc2cc3c(cn2)OCCO3)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To 10 mL of a dichloromethane solution containing 0.10 g of methyl 1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)-4-oxopiperidine-2-carboxylate, 2 mL of a dichloromethane solution containing 55 mg of 1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methaneamine and 32 μL of acetic acid were added at room temperature, and stirred at the same temperature for 1 hour, thereafter, 8 μL of acetic acid was further added, and stirred for 2.5 hours. To the reaction mixture, 59 mg of sodium triacetoxyborohydride was added, and stirred for 1 hour. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution and chloroform were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography [eluent; chloroform:methanol=50:1], to give 64 mg of methyl 4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylate as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]1[CH2:27][CH2:26][C:10]2([CH2:15][CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][CH2:11]2)[CH:9]=[CH:8]1)=[O:5])[CH3:2].[H][H]>C(O)C>[CH2:15]1[C:10]2([CH2:26][CH2:27][CH:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:9]2)[CH2:11][CH2:12][NH:13][CH2:14]1
Reactant: CCOC(=O)C=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)CC1CCC2(CCNCC2)CC1

Procedure:
9.6 g (26.0 mmol) of the protected Spiro compound from Step B were dissolved in 400 ml ethanol, and the solution was filled into a hydrogenation vessel followed by 2 g Pd(II) hydroxide on charcoal. The reaction was carried out at 40° C. and 1 atm hydrogen, and it was complete after about 40 hours. The catalyst was removed by filtration through silica gel, and the filtrate was concentrated under reduced pressure. The remaining oil was treated with dry ether, filtered, and the filtrate was acidified with ethereal hydrochloric acid. The hydrochloride of the title compound was collected by filtration, washed two times with ether, dissolved in water, and the solution was made alkaline with 2 N aqueous sodium hydroxide solution. After extraction with dichloromethane the organic layer was dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C1C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=Cc1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(N=Cc2cccc(Cl)c2)cn1

Procedure:
The starting material is prepared as follows: the mixture of 30.44 g of 5-aminopyridine-2-carboxylic acid methyl ester, 30.9 g of m-chlorobenzaldehyde, and 400 ml of benzene is refluxed for 3 days on a water-separating trap. The initial suspension eventually becomes a pale yellow solution, which is evaporated. The residual yellow solid is recrystallized from benzene-ethyl acetate-diethyl ether, to yield the 5-(m-chlorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester melting at 139°-142°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>Cl>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(CCCCOCCCCCCBr)cc1
Agent: Cl
Product: O=[N+]([O-])c1ccc(CCCCOCCCCCCNCc2ccccc2)cc1

Procedure:
1-[4-[(6-Bromohexyl)oxy]butyl]-4-nitrobenzene (8.0 g) was added dropwise to benzylamine (30 ml) at 110°. The solution was heated at 110°-120° for 2 h, treated with hydrochloric acid (2M; 200 ml), and extracted with ethyl acetate (2×150 ml). The organic extract was washed with aqueous sodium carbonate (150 ml) and brine (150 ml), dried and evaporated. The residue was purified by FCC eluting with ether to give the title compound as a pale yellow oil (5.9 g). T.l.c. Ether Rf 0.15.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28]/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[N:13](/[CH:28]=[CH:29]/[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:12]=1
Reactant: BrC/C=C/c1ccccc1
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccccc3c1)nn2/C=C/Cc1ccccc1
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and 1-((E)-3-bromoprop-1-enyl)benzene were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 378.2, found 378.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([N:15]([CH3:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:24][N:15]([C:13]1[CH:14]=[C:9]([O:7][CH2:3][C:4]#[C:5][CH3:6])[N:10]=[CH:11][N:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23]
Reactant: CC#CCO
Reactant: CN(c1cc(Cl)ncn1)c1cccc(F)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N(C)c2cccc(F)c2F)ncn1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.05 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes and then cooled to 0° C., to which 0.6 ml of a tetrahydrofuran solution containing 0.16 g of 4-chloro-6-(N-methyl-N-(2,3-difluorophenyl)amino)pyrimidine was slowly added dropwise, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.14 g of 4-(N-methyl-N-(2,3-difluorophenyl)amino)-6-(2-butynyloxy)pyrimidine (the present compound (66)), m.p.: 77.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:27]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8](=[S:30])[NH:7][C:6]=2[CH:27]=1
Reactant: Cc1cc2c(cc1C)N(C(=O)CN1CCN(C)CC1)c1ncccc1C(=O)N2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Cc1cc2c(cc1C)N(C(=O)CN1CCN(C)CC1)c1ncccc1C(=S)N2

Procedure:
In the manner given in Example 1, 8,9-dimethyl-6,11-dihydro-11-[(4-methylpiperazino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 8,9-dimethyl-6,11-dihydro-11-[(4-methylpiperazino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[NH:24][C:25]2[C:26]3[C:33]([CH3:34])=[C:32]([C:35]([NH2:37])=[O:36])[S:31][C:27]=3[N:28]=[CH:29][N:30]=2)[CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[F:23][C:21]1[CH:20]=[CH:19][C:18]([NH:24][C:25]2[C:26]3[C:33]([CH3:34])=[C:32]([C:35]([NH2:37])=[O:36])[S:31][C:27]=3[N:28]=[CH:29][N:30]=2)=[C:17]([O:16][C@H:13]2[CH2:14][CH2:15][C@H:10]([NH:9][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:11][CH2:12]2)[CH:22]=1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](N)CC3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](NC4CCN(C)CC4)CC3)c12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
0.019 g 1-methyl-4-piperidone in 1.5 ml MeOH followed by 1 drop acetic acid were added to a mixture of 0.070 g 4-(2-(trans-4-aminocyclohexyloxy)-4-fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxamide (cpd.15.2) in 2 ml methanol. Sodium cyanoborohydride was added when the mixture was stirred at rt for 40 min. After stirring at 50° C. for 3 h further 0.010 g 1-methyl-4-piperidone and 0.010 g sodium cyanoborohydride were added and heating was continued overnight.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[ClH:9]>CO.O=[Pt]=O>[ClH:9].[CH3:1][C@@H:2]1[NH:7][CH2:6][C@@H:5]([OH:8])[CH2:4][CH2:3]1
Reactant: Cc1ccc(O)cn1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: C[C@H]1CC[C@H](O)CN1
Temperature: 70 °C

Procedure:
To a solution of 6-methylpyridin-3-ol (20.0 g, 0.183 mol) in MeOH (200 mL) were added concentrated HCl (15.43 mL, 0.1850 mol) and PtO2 (2.40 g, 0.011 mol). The resulting mixture was heated to 70° C. at 50 PSI overnight. The reaction was filtered to remove the PtO2 and concentrated to a solid to provide ±trans-6-methylpiperidin-3-ol hydrochloride. The crude solid was taken on without further purification.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][NH2:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](Cl)=[O:23])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:21][C:22](=[O:23])[NH:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=1)[CH3:20]
Reactant: NCCOc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)NCCOc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 30 h
Yield: 53.2 %

Procedure:
5.5 g of 2-(p-benzoylphenoxy)ethylamine and 13 g of chloroformic acid ethyl ester are dissolved in 200 ml of acetone. 19.3 g of potassium carbonate are added to the solution and the mixture is heated under reflux with stirring for 30 hours. The mixture is then filtered and the crystals are washed with acetone. The filtrate is evaporated in vacuo. The residue is dissolved in ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in ether and crystallized by the addition of cyclohexane to yield 3.8 g (61%) of 2-(p-benzoylphenoxy)ethylcarbamic acid ethyl ester, m.p.--84°-86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:23][N:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:25]>>[CH3:23][N:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:25][C:20]([C:10]1[CH:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:9]=1)=[O:22]
Reactant: CN(N)c1ccccc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 1-methyl-1-phenyl-hydrazine (CAN 618-40-6) as starting materials; MS (EI) 436.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([O:29]CC)=[O:28])[CH2:22]2)=[O:20])=[CH:13][C:12]=1[Cl:32])[CH3:2].[OH-].[Na+].[OH-].[K+]>CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([OH:29])=[O:28])[CH2:22]2)=[O:20])=[CH:13][C:12]=1[Cl:32])[CH3:2]
Reactant: CCOC(=O)C1CCCN(C(=O)/C=C/c2ccc(Sc3ccccc3OCC)c(Cl)c2)C1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccccc1Sc1ccc(/C=C/C(=O)N2CCCC(C(=O)O)C2)cc1Cl
Reaction time: 8 h

Procedure:
The compound of Example 137 was hydrolyzed using an excess of aqueous 10% NaOH in methanol, stirring overnight. The reaction mixture was concentrated in vacuo, water was added, and the solution was extracted with ether. The mixture was acidified; the resultant solid was collected by filtration and dried overnight in a vacuum oven, giving a white solid, m.p. 166-171C. 1H-NMR (DMSO 300 MHz) δ 1.17 (t, J=7 Hz, 3H), broad peaks totaling 9 protons at 1.32-1.48, 1.51-1.78, 1.90-2.04, 2.25-2.50, 2.80-2.90, 2.95-3.17, 3.45-3.51, 3.95-4.19, 4.41-4.51, 4.06 (q, J=7 Hz, 1H), 6.80 (d, J=9 Hz, 1H), 7.01 (t, J=7 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 7.26-7.40 (m, 2H), 7.40-7.48 (m, 1H), 7.51 (dd, J=9 Hz, 2 Hz, 1H), 7.99 (d, J=9 Hz, 1H). Anal. Calcd. for C23H24ClNO4S: C, 61.94; H, 5.42; N, 3.14. Found: C, 61.75; H, 5.65; N, 3.15. The resultant acid (303 mg, 0.631 mmol) was dissolved in 3 mL MeOH. A KOH solution (38 mg, 0.595 mmol, of 87.6% KOH) in 1 ml MeOH was added. The resulting solution was concentrated in vacuo, and 5 mL ether was added. The mixture was stirred for one hour to form a powder, which was filtered and dried in the vacuum oven at 60C to yield 307 mg of a solid, water soluble product.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[S:18][CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[S:18][CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=3)[CH:15]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)c1csc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CC3)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1csc(-c2ccc3c(c2)NCC3)n1
Reaction time: 2.5 h
Yield: 170.1 %

Procedure:
To ethyl 2-(1-(tert-butoxycarbonyl)indolin-6-yl)thiazole-4-carboxylate (28C) (46 mg, 0.12 mmol) was added DCM (5 ml) and TFA (1 ml) and stirred for 2.5 hours. The mixture was concentrated under reduced pressure to provide 56 mg of the desired product ethyl 2-(indolin-6-yl)thiazole-4-carboxylate (28D): LC/MS (APCI): m/z 275.0 (M+H).