Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:42][C:43]([O:45]C)=[O:44])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13](S(C3C=CC(Cl)=CC=3Cl)(=O)=O)[C:14]([CH3:16])=[N:15][C:11]=2[C:10]=1[NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])(=[O:33])=[O:32].[Li+].[OH-].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:42][C:43]([OH:45])=[O:44])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:29]=[CH:28][C:12]2[NH:13][C:14]([CH3:16])=[N:15][C:11]=2[C:10]=1[NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])(=[O:32])=[O:33]
Reactant: COC(=O)Cc1ccc(Oc2ccc3c(nc(C)n3S(=O)(=O)c3ccc(Cl)cc3Cl)c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(NS(=O)(=O)c3ccc(Cl)cc3Cl)c(Oc3ccc(CC(=O)O)cc3Cl)ccc2[nH]1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Under an N2 atmosphere, methyl 2-(3-chloro-4-(4-(2,4-dichlorophenylsulfonamido)-1-(2,4-dichlorophenylsulfonyl)-2-methyl-1H-benzo[d]imidazol-5-yloxy)phenyl)acetate (0.097 g, 0.127 mmol) was dissolved in tetrahydrofuran (1.5 mL) and 1 N LiOH (1.5 mL) was added. The reaction was stirred at 50° C. for 3 h. The reaction was diluted with water, made acidic with 1N HCl to pH 4, and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound. LC-MS ESI (pos.) m/z: 541.9 (M+H). 1H NMR (400 MHz) (DMSOd-6) δ 7.63 (d, J=8.5 Hz, 1H); 7.46 (bs, 1H); 7.31-7.22 (m, 3H); 6.94 (d, J=7.6 Hz, 1H); 6.46 (bs, 1H); 6.29 (bs, 1H) 3.51 (s, 2H); 2.48 (s, 3H).
Reaction SMILES: CC([C:10]1[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)(C)C1C=CC=CC=1.CC1C=CC(CCl)=CC=1>[Cl-].[Zn+2].[Cl-].[N+](C)([O-])=O>[C:15]([OH:17])(=[O:16])[C:14]1[C:13](=[CH:12][CH:11]=[CH:10][CH:18]=1)[OH:19]
Reactant: CC(C)(c1ccccc1)c1ccc(O)c(C(=O)O)c1
Agent: Cc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C[N+](=O)[O-]
Product: O=C(O)c1ccccc1O
Reaction time: 2 h

Procedure:
A glass-made reactor was charged with 5.1 g (0.02 mole) of 5-(α, α-dimethylbenzyl)salicylic acid, 50 ml of nitromethane, and as a catalyst, 1.4 g of anhydrous zinc chloride. The resultant mixture was maintained at 95° C. under stirring. At the same temperature, 22.5 g (0.16 mole) of p-methylbenzyl chloride was added dropwise over 10 hours to conduct a reaction. After completion of the dropwise addition, the reaction mixture was aged for 2 hours at the same temperature to complete the reaction. The weight average molecular weight of the thus-obtained resin was 2400.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:21]1[N:22]=[C:23]([NH2:39])[C:24]2[N:25]=[CH:26][N:27]([C:37]=2[N:38]=1)[C@@H:28]1[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]1[OH:30]>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]([N:7]2[CH2:6][CH2:5][CH:4]([CH2:1][C:2]#[C:3][C:21]3[N:22]=[C:23]([NH2:39])[C:24]4[N:25]=[CH:26][N:27]([C:37]=4[N:38]=3)[C@@H:28]3[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]3[OH:30])[CH2:9][CH2:8]2)=[O:11])=[CH:14][CH:15]=1
Reactant: C#CCC1CCN(C(=O)Oc2ccc(C)cc2)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Cc1ccc(OC(=O)N2CCC(CC#Cc3nc(N)c4ncn([C@@H]5O[C@H](CO)[C@@H](O)[C@H]5O)c4n3)CC2)cc1

Procedure:
Batch: AB-10-019. 4-methylphenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-105 (0.548 g, 2.130 mmol) was added to a solution of 2-iodoadenosine (0.629 g, 1.600 mmol) according to general procedure 2. Yield: 0.236 g, 28%. 1H NMR (CD3OD) δ 8.29 (s, 1H), 7.14-6.92 (2×m, 4H), 5.95 (d, 1H), 4.75 (m, 2H), 4.34-4.16 (2×m, 3H), 3.91-3.71 (2×d, 2H), 3.10-2.90 (2×bt, 4H), 2.28 (s, 3H), 2.43 (d, 5H), 1.92-1.41 (2×m, 5H). m/z MH+=523.16. HPLC rt=6.8 min.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:11]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C@H:32]([C:34]([N:36]1[CH2:47][CH2:46][CH2:45][C@H:37]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:35])[CH3:33].C(O)C.C([BH3-])#N.[Na+]>O1CCCC1>[C:1]([NH:9][C@@H:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:11]([S:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH2:12][NH:31][C@H:32]([C:34]([N:36]1[CH2:47][CH2:46][CH2:45][C@H:37]1[C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])=[O:35])[CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: COc1ccc(CS[C@H](C=O)C(Cc2ccccc2)NC(=O)c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CSC(CN[C@@H](C)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)[C@H](Cc2ccccc2)NC(=O)c2ccccc2)cc1
Reaction time: 2.5 h

Procedure:
A mixture of (S)-β-(benzoylamino)-α-[[(4-methoxyphenyl)methyl]thio]-benzenebutanal (isomer A) (0.45 g., 1.07 mmole), L-alanyl-L-proline, 1,1-dimethylethyl ester (0.78 g., 3.21 mmole), and crushed 3A° molecular sieves (2 g.) in tetrahydrofuran (5 ml.) and absolute ethanol (5 ml.) is stirred at room temperature under argon. After 2.5 hours, sodium cyanoborohydride (0.20 g., 3 eq.) is added and stirring continued for 15 hours. The reaction mixture is filtered to remove the sieves and the filtrate is diluted with ethyl acetate and washed with water, 1N hydrochloric acid (twice), 1N sodium bicarbonate, and brine. After drying over anhydrous MgSO4, the solvent is removed to give the desired product, as a mixture of diastereomers, as a pale yellow oil. TLC (silica gel, benzene:acetone, 4:1) isomer A at Rf =0.30 and isomer B at Rf =0.13. Flash chromatography (silica gel LPS-1; benzene:acetone, 7:3) affords impure product (isomer A). Repeated flash chromatography (silica gel LPS-1; ethyl acetate:benzene, 6:4) gives 0.20 g. of 1-[N-[(3S)-3-(benzoylamino)-2-[[(4-methoxyphenyl)methyl]thio]-4-phenylbutyl]-L-alanyl]-L-proline, 1,1-dimethylethyl ester (isomer A) as a nearly colorless oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH2:21])=[N+:2]=[N-:3].[C:22]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][O:24][CH2:23]1>ClCCl.O>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:26](=[O:27])[CH2:25][O:24][CH2:23][C:22]([OH:29])=[O:28])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCN
Reactant: O=C1COCC(=O)O1
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NCCOCCOCCOCCOCCOCCNC(=O)COCC(=O)O
Reaction time: 8 h

Procedure:
To a solution of 17-azido-3,6,9,12,15-pentaoxaheptadecanamine (15 g, 50 mmol) in dichloromethane (100 mL) was added diglycolic anhydride (Acros, 6.4 g, 55 mmol). The reaction mixture was stirred overnight. The reaction was monitored by ESI-MS analysis, and more reagents were added to drive the reaction to completion. The solution was concentrated to give a yellow residue which was dissolved in water (250 mL). The product was isolated from the aqueous phase by continuous extraction with dichloromethane overnight. Drying and evaporation of the solvent gave a yield of 18 g (85%). The product was characterized by ESI-MS analysis (MH+ calculated: 423.20. found 423.4). The product was used in the next step without further purification.
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:26][CH2:25][CH:24]([CH3:27])[NH:23][C:22]=2[CH:28]=1>>[CH3:16][O:17][C:18]1[C:28]2[C:11](=[O:13])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:23]3[CH:24]([CH3:27])[CH2:25][O:26][C:21]([C:22]=23)=[CH:20][CH:19]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc2c(c1)NC(C)CO2
Product: CCOC(=O)c1cn2c3c(ccc(OC)c3c1=O)OCC2C

Procedure:
Using the method of Example 1 diethyl ethoxymethylene malonate is reacted with 3,4-dihydro-6-methoxy-3-methyl-2H-1,4-benzoxazine and the product reacted with polyphosphoric acid to provide ethyl 2,3-dihydro-8-methoxy-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate, m.p. 165°-168° C.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH:16]1[C:24]2[C:19](=[CH:20][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:23]=2)[CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:21]3[CH:20]=[C:19]4[C:24](=[CH:23][CH:22]=3)[NH:16][N:17]=[CH:18]4)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCNc1ccc2ncc(-c3ccc4[nH]ncc4c3)n2n1
Yield: 65.3 %

Procedure:
A mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (140 mg, 0.50 mmol), (1H-indazole-5-boronic acid pinacol ester (150 mg, 0.60 mmol), dichloro-bis(triphenylphosphino) palladium (II) (20 mg, 0.025 mmol), potassium carbonate (110 mg, 0.75 mmol), acetonitrile (1.5 mL) and H2O (0.5 mL) was heated in a sealed conical vessel at 160° C. for 1000 s by microwave irradiation. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 mL). The combined organic layers were concentrated under reduced pressure to afford an oil that was purified by reverse phase HPLC to afford butyl-[3-(1H-indazol-5-yl)-imidazo[1,2-b]pyridazin-6-yl]-amine (100 mg, 65%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.62-8.68 (m, 1H), 8.13-8.20 (m, 2H), 8.02 (dd, J=8.8, 1.5 Hz, 1H), 7.94 (d, J=9.9 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.21 (d, J=9.9 Hz, 1H), 3.43 (t, J=7.2 Hz, 2H), 1.66-1.79 (m, 2H), 1.49 (dq, J=15.1, 7.4 Hz, 2H), 0.99 (t, J=7.5 Hz, 3H); LCMS (ESI) m/e 307.2 [(M+H)+, calcd for C17H19N6 307.2].
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:23]([O:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7])=[CH:4][CH:3]=1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)C(=O)OCC)cc1
Temperature: 40 °C

Procedure:
1.62 g (8.39 mmol) ethyl 4-hydroxybenzoylformate and 5.79 g (42 mmol) K2CO3 are dissolved in 70 ml acetone. 1.22 g (10.1 mmol) allyl bromide is added dropwise at room temperature. The mixture is heated at 40° C. for 3.25 hours under nitrogen atmosphere. The mixture is then filtered and evaporated. The phases are separated and water is extracted with toluene. The organic phases are dried over magnesium sulfate. Evaporation of the solvent and chromatography (eluent: hexane ethyl acetate 3:1) give 1.39 g (71 wt %) of a yellow oil.
Reaction SMILES: [NH:1]([C:8]1[CH2:17][C:16]([C:18]([O:20]C)=O)=[C:15]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:14][C:9]=1[C:10]([O:12]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C)C=O>[CH:26]1[CH:27]=[C:28]2[C:18]([C:16]3[C:15]([NH:22][C:23]2=[CH:24][CH:25]=1)=[CH:14][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:17]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:12])=[O:20]
Reactant: COC(=O)C1=C(Nc2ccccc2)CC(C(=O)OC)=C(Nc2ccccc2)C1
Solvent: CN(C)C=O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Yield: 90.5 %

Procedure:
Using a Venturi nozzle, per hour a solution of 300 g of dimethyl 2,5-dianilino-3,6-dihydroterephthalate and 400 ml of N,N-dimethylformamide was nozzled into a preheated gas stream of nitrogen (1.2 m3 /h) and air (300 l/h) at 500° C. This gas-liquid mixture was introduced tangentially into a tubular reactor (50 mm in diameter, 400 mm in length) at 575° C. A conventional workup gave 224 g of crude quinacridone per hour of 98% purity (according to UV).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH3:21][C:22]1[CH:38]=[CH:37][CH:36]=[CH:35][C:23]=1[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)=[O:25].CO[C:41](=O)[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[CH:43]=1>C1COCC1.CCCCCC>[CH3:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:26]2[C:41]([C:42]3[CH:43]=[C:44]([CH3:48])[CH:45]=[CH:46][CH:47]=3)=[CH:21][C:22]3[C:23](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:24]2=[O:25])=[CH:33][CH:32]=1
Reactant: Cc1ccc(CNC(=O)c2ccccc2C)cc1
Reactant: COC(=O)c1cccc(C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Cn2c(-c3cccc(C)c3)cc3ccccc3c2=O)cc1
Temperature: 0 °C
Reaction time: 0.92 h
Yield: 46.8 %

Procedure:
To a solution of diisopropylamine (1.2 mL, 8.56 mmol) in THF (15 mL) at 0° C. was added n-butyllithium (5.2 mL of a 1.6 M solution in hexane, 8.32 mmol). After stirring at 0° C. for 10 minutes the resulting lithium diisopropylamide solution was treated with a solution of 2-methyl-N-(4-methylbenzyl)benzamide (616 mg, 2.57 mmol) in THF (20 mL) over 15 min. The resulting deep brown-red solution was stirred at 0° C. for 55 minutes at which time it was treated with a solution of 3-methylbenzoic acid methyl ester (0.39 mL, 2.76 mmol) in THF (20 mL) over 20 minutes. After an additional 1 hour at 0° C. the reaction was quenched by the addition of 3N HCl (25 mL). The biphasic mixture was then heated to reflux with vigorous stirring. After 75 minutes at reflux the reaction mixture was allowed to cool to ambient temperature overnight. After cooling overnight, the reaction was concentrated to remove most of the THF. The resulting residue was diluted with ether (100 mL), and water (50 mL), and then basified by careful addition of solid Na2CO3. The basic aqueous was extracted with ether (3×40 mL), combined organics were washed with brine (50 mL), dried over Na2CO3, filtered, and concentrated to afford a yellow oil. The crude product was purified by silica gel column chromatography on a Jones Flashmaster instrument eluting with a gradient from 0% to 6% ethyl acetate/hexane on a 50 g silica column. The product peak was collected to afford 2-(4-methylbenzyl)-3-m-tolyl-2H-isoquinolin-1-one (408 mg, 47% yield) as a yellow oil that slowly solidified to a waxy solid:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:9]2)=[CH:6][C:5]([C:26]#[N:27])=[CH:4][C:3]=1[NH:28][C:29]1[N:34]=[C:33]([N:35]([CH:43]2[CH2:45][CH2:44]2)C(=O)OC(C)(C)C)[C:32]2=[N:46][CH:47]=[C:48]([C:49]#[N:50])[N:31]2[N:30]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:9]2)=[CH:6][C:5]([C:26]#[N:27])=[CH:4][C:3]=1[NH:28][C:29]1[N:34]=[C:33]([NH:35][CH:43]2[CH2:44][CH2:45]2)[C:32]2=[N:46][CH:47]=[C:48]([C:49]#[N:50])[N:31]2[N:30]=1
Reactant: CC(C)(C)OC(=O)N(c1nc(Nc2cc(C#N)cc(N3CCN(C4COC4)C(C(=O)N4CCOCC4)C3)c2Cl)nn2c(C#N)cnc12)C1CC1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCN(C3COC3)C(C(=O)N3CCOCC3)C2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
(+/−) Tert-butyl (2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-7-cyanoimidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl)carbamate (40 mg, 0.057 mmol) was taken up in DCE (275 μL) and anisole (31.0 μL, 0.284 mmol) was added. The reaction was cooled to 0° C., and TFA (92 μL, 1.193 mmol) was added. The reaction was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for 1.5 h. The solvent was removed in vacuo and the material was azeotroped 2× with toluene to remove the excess TFA. The crude material was purified by preparative HPLC to provide (+/−)2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.9 mg).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6](C)[C:7](=[O:16])[N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][N:39]([C:42](=[O:44])[CH3:43])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1>CN(C=O)C.CCOC(C)=O>[C:42]([N:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:34]=[CH:35][C:30]([NH:29][C:2]3[N:10]=[C:9]4[C:5]([NH:6][C:7](=[O:16])[N:8]4[CH:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[CH:4][N:3]=3)=[CH:31][CH:32]=2)[CH2:41][CH2:40]1)(=[O:44])[CH3:43]
Reactant: CCC(CC)n1c(=O)n(C)c2cnc(Cl)nc21
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)n1c(=O)[nH]c2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Temperature: 140 °C
Yield: 29.5 %

Procedure:
To a mixture of 2-chloro-9-(1-ethyl-propyl)-7-methyl-7,9-dihydro-purin-8-one (102 mg, 0.4 mmol) and TsOH (1.6 mL, 0.2 M in 1,4-dioxane) in DMF (0.25 mL) is added 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (105 mg, 0.5 mmol). The reaction mixture is sealed in a microwave reactor and heated at 140° C. for 30 min. The mixture is diluted with EtOAc and washed with NaHCO3 aqueous solution and brine. The organics are dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative HPLC to give 50 mg of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-9-(1-ethyl-propyl)-7,9-dihydro-purin-8-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][O:12][C:13](OC)(OC)OC.C(O)(=O)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:13]([O:12][CH3:11])[N:8]([CH3:9])[C:5]2=[N:6][CH:7]=1
Reactant: COC(OC)(OC)OC
Reactant: CNc1ncc(Br)cc1N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1nc2cc(Br)cnc2n1C

Procedure:
A solution of 5-bromo-N*2*-methyl-pyridine-2,3-diamine (Stage 67.1.4, 960 mg, 4.75 mmol) and tetramethylorthocarbonate (Aldrich, Buchs, Switzerland, 2 ml, 14.7 mmol) and acetic acid (0.273 ml, 4.75 mmol) was stirred for 90 min at 100° C. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. The aqueous layer was extracted with EtOAc and the combined organic layers washed with saturated aqueous NaHCO3 and with brine, then dried over Na2SO4, filtered and evaporated. The crude product was dry loaded on silica gel and purified by MPLC (DCM/MeOH 0%-4%) to give the title compound as a green solid. (HPLC: tR 2.83 min (Method A); M+H=242, 244 MS-ES).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH3:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]1[C:41]([OH:43])=O.C(N=C=NC(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][N:30]([CH3:31])[C:41]([C:33]2[NH:32][C:40]3[C:35]([CH:34]=2)=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:43])(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2cc3ccccc3[nH]2)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.2 %

Procedure:
To a solution of 0.05 g (0.114 mmol) of N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide prepared as described in step A of Example 28 in 2 mL of CH2Cl2 and 0.1 mL DMF, 0.018 g (0.114 mmol) of indole-2-carboxylic acid and 0.021 g (0.142 mmol) of 1,3-diisopropylcarbodiimide were added. The mixture was then stirred at room temperature for 12 hr and evaporated. The residue was purified by reverse phase preparative HPLC on a 30×500 mm ODS S10 column using 80% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 20% solvent A (10% MeOH, 90% H2O, 0.1% TFA). The appropriate fractions were collected and neutralized with aqueous sodium bicarbonate to pH 7 and concentrated to 10 mL. The solution was then acidified to pH 4 using aqueous sodium bisulfate and the white solid was filtered and dried to provide 0.024 g (36%) of the title compound of this Example as a white solid. m.p. 135°-145° C.
Reaction SMILES: [C:1]([S:9]CC(O)=O)(=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:15]([NH:19][NH2:20])([CH3:18])([CH3:17])[CH3:16].O>N1C=CC=CC=1>[C:15]([NH:19][NH:20][C:1](=[S:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)NN
Reactant: O=C(O)CSC(=S)c1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)NNC(=S)c1ccccc1
Temperature: 120 °C

Procedure:
S-(thiobenzoyl)thioglycolic acid (3.0 g) was dissolved in 20 ml pyridine, treated with t-butyl hydrazine hydrochloride (excess, ca. 4 g) and then was heated at ca. 120° C. for 14 hours. Water (120 ml) was added and the mixture was extracted with ether. The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to give crude N'-t-butyl-N-(thiobenzoyl)hydrazine as a viscous yellow oil.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](I)[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH2:9][C:10]1=[O:18])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CI
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1
Product: CC(C)CN1C(=O)CN=C(c2ccccc2)c2ccccc21

Procedure:
1,3-Dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (prepared according to the procedure of M. G. Bock et al., J. Org. Chem. 1987, 52, 3232-3239) was alkylated with isobutyl iodide using General Procedure 8-G to afford 1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][C@@H:6]([C:15]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:26])[NH:20]2)[O:7][Si](C(C)(C)C)(C)C.[ClH:27]>CO>[ClH:27].[NH2:4][CH2:5][C@@H:6]([C:15]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:26])[NH:20]2)[OH:7]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
(R)-5-(2-Amino-1-(tert-butyldimethylsilyloxy)ethyl)-8-hydroxyquinolin-2(1H)-one formate (0.23 g, 0.61 mmol) was dissolved in hydrochloric acid (5 mL, 4 M solution in dioxane) and methanol (5 mL). The reaction mixture was stirred at RT for 16 hours before concentrating in vacuo. The resulting residue was washed with ethyl acetate and dried in a vacuum oven for 18 hours to afford the title compound (0.15 g, 99%).