Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[CH2:16]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15])[CH3:17]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCCN2CCN(c3ccc(F)cc3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-fluorophenyl)-piperazine.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[C:29]([F:35])=[CH:30][CH:31]=[CH:32][C:33]=2[F:34])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3c(F)cccc3F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
Lithium hydroxide monohydrate (0.01 g, 0.26 mmol) was added to a stirred solution of {6-chloro-4-[4-(2,6-difluoro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.032 g, 0.064 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-4-[4-(2,6-difluoro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.029 g, 93%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (br. s, 1 H) 8.18 (d, J=7.83 Hz, 2 H) 7.98 (d, J=8.30 Hz, 1 H) 7.92 (s, 1 H) 7.81-7.89 (m, 1 H) 7.59 (d, J=7.82 Hz, 2 H) 7.49 (dd, J=8.80, 1.90 Hz, 1 H) 7.35-7.44 (m, 2 H) 6.97 (s, 1 H) 3.85 (s, 2 H) 2.04 (s, 3 H). MS calcd. for C25H16ClF2O4S [(M−H)−] 485, obsd. 485.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:33])([F:32])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28][CH2:29][CH2:30]O)=[CH:22][CH:21]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:32])[F:33])=[CH:21][CH:22]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2cc(O)ccc21
Reactant: OCCCC#Cc1ccc(OC(F)(F)F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2cc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)ccc21

Procedure:
In analogy to the procedure described for example 1 d], (5-hydroxy-indol-1-yl)-acetic acid ethyl ester was reacted with 5-(4-trifluoromethoxy-phenyl)-pent-4-yn-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[CH3:20][NH:21][C:22]1[N:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][N:23]=1.C(O)(=O)C.C([BH3-])#N>C(O)C>[F:1][C:2]1[N:7]=[C:6]([NH:8][CH2:28][C:25]2[CH:24]=[N:23][C:22]([NH:21][CH3:20])=[N:27][CH:26]=2)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Reactant: CNc1ncc(C=O)cn1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1ncc(CNc2ccc(Cc3c[nH]c4ncc(C)cc34)c(F)n2)cn1

Procedure:
In a 2 mL microwave vial, 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 9.72 mg, 0.04 mmol) and 2-methylamino-pyrimidine-5-carbaldehyde (138, 11.0 mg, 0.08 mmol) were dissolved in 600 μL of 95:5 ethanol:acetic acid, and silica supported cyanoborohydride (50 mg, 1 mmol/g, 0.05 mmol) was added. The reaction was irradiated for 10 minutes at 160° C. in a microwave. The vial was centrifuged to condense the silica and the supernatant was removed by pipette into another vial. The residual silica was rinsed with 500 μL of ethanol, centrifuged and the supernatant added to the first supernatant. The solvents were removed under vacuum and the resulting material dissolved in 400 μL of dimethyl sulfoxide for purification by HPLC. Samples were purified on Phenomenex C18 column (50 mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H+]+=378.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]([CH3:27])([CH3:26])[CH2:10]2)[N:5]=[C:4]([O:28][CH:29]2[CH2:34][C:33]([CH3:36])([CH3:35])[N:32]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:31]([CH3:47])([CH3:46])[CH2:30]2)[N:3]=1.[CH2:48]([CH2:50][NH2:51])[OH:49]>>[OH:49][CH2:48][CH2:50][NH:51][C:2]1[N:3]=[C:4]([O:28][CH:29]2[CH2:30][C:31]([CH3:46])([CH3:47])[N:32]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:33]([CH3:35])([CH3:36])[CH2:34]2)[N:5]=[C:6]([O:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]([CH3:26])([CH3:27])[CH2:10]2)[N:7]=1
Reactant: CCCCCCCCON1C(C)(C)CC(Oc2nc(Cl)nc(OC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Reactant: NCCO
Product: CCCCCCCCON1C(C)(C)CC(Oc2nc(NCCO)nc(OC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,3,5-triazine with ethanolamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:13]=[C:14]([OH:22])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:22][C:14]1[CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=[C:12]([F:11])[CH:13]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Product: O=Cc1ccc(Oc2cc(F)cc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 3,4-difluorobenzaldehyde and 3-fluoro-5-(trifluoromethyl)phenol.
Reaction SMILES: C(S)C.C[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1>CN(C)C=O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:19][C:20]([OH:22])=[O:21])=[CH:8][CH:7]=1
Reactant: COc1ccc(CCC(CC(=O)O)CC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCS
Product: O=C(O)CC(CCc1ccc(O)cc1)CC(=O)O
Temperature: 25 °C
Yield: 88 %

Procedure:
To a suspension of 57% sodium hydride-paraffin (2.2 g) in dry dimethylformamide (70 ml) in an atmosphere of nitrogen is slowly added ethanethiol (4.0 ml). The mixture is stirred at room temperature until a clear solution results. To this solution is added a solution of 3-[2-(4-methoxyphenyl)ethyl]glutaric acid (1.2 g) in dry dimethylformamide (10 ml) and the mixture is heated with stirring in a bath at 165° C. for 6.0 hours. The mixture is then evaporated to dryness in vacuo and the resulting residue is dissolved in water (50 ml), extracted with ether (two 50 ml portions) and the ether extract is discarded. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried with anhydrous magnesium sulfate, and evaporated to a residue. Crystallization of this from chloroform-hexane affords 1.0 g of the title compound, melting point 142°-144° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[CH:24]=O)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.CO.[CH3:31][NH:32][CH3:33].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:31][N:32]([CH2:24][C:23]1[CH:22]=[C:21]([CH:13]2[NH:12][C:7]3[C:6]4[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][CH:8]=3)[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:33]
Reactant: CNC
Reactant: O=Cc1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)Cc1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 61.3 %

Procedure:
A mixture of 3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (50 mg, 0.14 mmol) and IM dimethylamine methanol solution (0.5 ml, 0.41 mmol) in methanol (10 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium cyanoborohydride (13 mg, 0.20 mmol) and acetic acid (40.8 mg, 0.68 mmol) was added. After the addition, the mixture was stirred at 0° C. for 2 hr. Methanol was removed under reduced pressure. The residue was resolved with 1N hydrochloric acid and washed with ethyl acetate. The mother liquor was adjusted to pH=8 and extracted with ethyl acetate. The solvent was removed to give 8-(3-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (34 mg, yield 64%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.17 (s, 6H), 3.17-3.41 (q, 2H), 4.31 (d, J=8.0 Hz, 1H), 4.74 (d, J=8.0 Hz, 1H), 7.08-7.10 (m, 2H), 7.13-7.25 (m, 8H), 7.55-7.57 (d, J=8.0 Hz, 1H), 7.61-7.65 (m, 1H). LC-MS (ESI) m/z: 397 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[N+:21]([O-])=O)[CH2:7][CH2:6]1)=[O:4].[H][H]>[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[NH2:21])[CH2:9][CH2:10]1)=[O:4]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(NC[C@H]2CC[C@H](C(=O)OC)CC2)c1
Agent: [Pd]
Product: COc1ccc(N)c(NC[C@H]2CC[C@H](C(=O)OC)CC2)c1

Procedure:
trans-4-[(5-Methoxy-2-nitro-phenylamino)-methyl]cyclohexane carboxylic acid methyl ester (800 mg, 2.48 mmol) was dissolved in 10 ml of EtAc mixed with 80 mg of Pd/C (10%, wet) and transferred in a Eyela reactor. The mixture was left overnight under 5 bar of hydrogen, then the solution was filtered through cellulose and the solvent removed under reduced pressure to give the titled compound as a brown solid. (700 mg, yield=96%)
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)[C:7]2=[O:13].[F:26][C:27]1[CH:28]=[C:29]([CH2:37][C:38](O)=[O:39])[CH:30]=[CH:31][C:32]=1[C:33]([F:36])([F:35])[F:34].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[F:26][C:27]1[CH:28]=[C:29]([CH2:37][C:38]([NH:1][C:2]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:7]3=[O:13])=[O:39])[CH:30]=[CH:31][C:32]=1[C:33]([F:35])([F:36])[F:34]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: Cc1ccc2c(=O)n([C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc2c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(=O)n([C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A reaction vial was charged with (S)-tert-butyl 3-(5-amino-6-methyl-1-oxoisoquinolin-2(1H)-yl)pyrrolidine-1-carboxylate (150.00 mg, 0.043678 mmol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (116.4 mg, 0.05241 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (420 mg, 1.1 mmol), N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) and N,N-dimethylformamide (2 mL, 20 mmol) and the reaction was stirred at 45° C. overnight. The solvent was removed under reduced pressure and the residue purified by flash chromatography to afford the product as light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=[O:6].[Cl:11]C1C=CC=CC=1Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[C:5]([Cl:11])=[O:6]
Reactant: Cc1cc(C)cc(C=O)c1
Reactant: Clc1ccccc1Cl
Product: Cc1cc(C)cc(C(=O)Cl)c1
Reaction time: 6 h
Yield: 70 %

Procedure:
Into a 2-L three-necked flask equipped with a gas blowing tube, a reflux condenser and a stirrer, were charged 269.7 g (2 mol) of 3,5-dimehtylbenzaldehyde and 800 g of o-dichlorobenzene. The temperature of the reaction system was controlled to 5° C. while introducing a nitrogen gas. After bubbling the reaction solution by blowing a nitrogen gas for one hour, the feed of nitrogen was stopped and the feed of chlorine was started. Simultaneously with the feed of chlorine, the irradiation of light from a mercury lamp was started. The photochlorination was completed after 6 h. The quantitative analysis by gas chromatography showed the production of 1.4 mol of 3,5-dimethylbenzoyl chloride (yield: 70%). By vacuum distillation, 236 g (1.4 mol) of 3,5-dimethylbenzoyl chloride was isolated (yield: 68%). The results of total elements analysis by ICP showed that a total content of residual group 3 to group 12 metals was 500 ppm or lower in which the highest was 10 ppm of Fe and the second highest was 30 ppm of Zn.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH3:12][C:13]1([CH2:16]OC2C=CC=CC=2NC(=O)C2C=CC=CC=2)[CH2:15][O:14]1>>[CH3:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[O:1][CH2:12][C:13]1([CH3:16])[CH2:15][O:14]1
Reactant: CC1(COc2ccccc2NC(=O)c2ccccc2)CO1
Reactant: CNC(=O)c1ccccc1O
Product: CNC(=O)c1ccccc1OCC1(C)CO1

Procedure:
N-Methyl-2-[(2-methyl-2-oxiranyl)methoxy]benzamide was prepared from 2-hydroxy-N-methylbenzamide (prepared according to Cohen et al, J. Am. Chem. Soc., 1998, 20, 6277-6286.) according to the method described for N-{2-[(2-methyl-2-oxiranyl)methoxy]phenyl}benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[NH:26][C:25](/[CH:27]=[CH:28]/[CH2:29][NH:30]C(=O)OC(C)(C)C)=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.[OH-].[Na+]>O1CCCC1>[NH2:30][CH2:29]/[CH:28]=[CH:27]/[C:25]1[NH:26][C:19]2[C:18]([NH:17][C:4]3[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:23][CH:22]=[N:21][C:20]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)NC/C=C/c1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC/C=C/c1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of tert-butyl (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]prop-2-enylcarbamate (150 mg) in tetrahydrofuran (6.0 mL) was added 2N hydrochloric acid (3.0 mL) at room temperature and the mixture was stirred at 60° C. for 2 hrs. 1N Aqueous sodium hydroxide solution was added to alkalize the reaction system. After extraction with chloroform, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resultant crystals were collected by filtration. The crystals were washed with diisopropyl ether to give the title compound (104 mg) as pale-brown powder crystals.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41]C(F)=CC=2)=S)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1.Cl.FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1[O:53]C1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1>>[CH:37]1([CH2:36][C:35]([NH:34][C:32]([NH:31][C:6]2[CH:7]=[CH:8][C:9]([O:10][C:11]3[C:16]4=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]5[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]5)=[CH:19][N:15]4[N:14]=[CH:13][N:12]=3)=[C:4]([F:3])[CH:5]=2)=[O:53])=[O:44])[CH2:42][CH2:41]1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)NC(=O)CC4CC4)cc3F)c12

Procedure:
Prepared in a similar manner as Example 264 using Compound B of Example and Compound A of Example 279 (21.0 mg, 81%). 1H NMR (CD3OD) δ 7.81 (s, 1H), 7.74 (d, 1H, J=5.5 Hz), 7.25 (m, 3H), 4.18 (t, 2H, J=5.5 Hz), 3.35 (t, 2H, J=1.7 Hz), 2.90 (t, 2H, J=5.5 Hz), 2.74–2.54 (m, 4H), 2.45 (s, 3H), 2.33 (t, 4H, J=2.8 Hz), 1.12 (m, 1H), 0.67–0.64 (m, 2H), 0.29–0.25 (m, 2H); MS(ESI+) m/z 529.3 (M+H)+.
Reaction SMILES: [C:1]1([CH2:13][CH2:14][NH2:15])[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]3[O:10][CH2:11][CH2:12][C:6]=3[C:5]=12.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]1([CH2:13][CH2:14][NH:15][C:23](=[O:25])[CH3:24])[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]3[O:10][CH2:11][CH2:12][C:6]=3[C:5]=12
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1cnn2ccc3c(c12)CCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1cnn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of 2-(8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)ethanamine (75.0 mg, 0.369 mmol) and triethylamine (105 μL, 0.753 mmol) in tetrahydrofuran (4 mL) was added acetic anhydride (70.0 μL, 0.741 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous sodium hydrogen carbonate solution (50 μL) was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) and recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (42.1 mg, yield 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[N:11]=1
Reactant: CN1CCNCC1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Product: CN1CCN(c2nc(Cc3cccc(Cl)c3)[nH]c(=O)c2C#N)CC1

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 343 mg (3.43 mmol) of N-methylpiperazine to give 101 mg (84% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:1])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: CN(c1ccccc1)c1cccc(C(=O)O)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 3 %

Procedure:
A solution of 3-(methyl(phenyl)amino)benzoic acid (0.056 g, 0.246 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.057 g; 0.246 mmol), HATU (0.102 g; 0.271 mmol) and N,N-diisopropylethylamine (0.106 mL; 0.616 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.003 g (3%) of the title compound as a white solid.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])=[CH:25][CH:24]=1>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:31])=[CH:27][CH:28]=1)(=[O:4])[CH3:2]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1CN
Reactant: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1CNC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
After dissolving N-[4-(6-aminomethyl-7-methoxy-quinolin-4-yloxy)phenyl]-N′-phenylurea trifluoroacetate (40 mg) in pyridine (1.0 ml) and acetic anhydride (1.0 ml), the solution was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and the obtained crude product was crystallized with ethyl acetate to obtain the title compound (13 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]=[C:12]=S)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.Cl.[NH2:23][CH2:24][C@@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:11][C:12]3[O:33][C@:25]4([CH2:24][N:23]=3)[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]4)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: Fc1ccc2c(N=C=S)n[nH]c2c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1ccc2c(NC3=NC[C@@]4(CN5CCC4CC5)O3)n[nH]c2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To 6-fluoro-3-isothiocyanato-1H-indazole (0.20 g, 1.04 mmol) in DMF (15 mL) was added triethylamine (0.43 mL, 3.11 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.26 g, 1.14 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and treated with N,N′-diisopropylcarbodiimide (0.48 mL, 3.11 mmol). The reaction was then heated to 70° C. for 2 hours. The reaction was cooled to ambient temperature and concentrated. The crude product was purified by column chromatography (85% chloroform, 14% methanol, 1% ammonium hydroxide) to afford (R)—N-(6-fluoro-1H-indazol-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.22 g, 0.66 mmol, 64% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 12.16 (s, 1 H), 8.00 (s, 1 H), 7.59-7.67 (m, 1H), 7.09 (dd, J=9.77, 2.14 Hz, 1 H), 6.81-6.88 (m, 1 H), 3.81 (d, J=9.16 Hz, 1 H), 3.56 (d, J=8.85 Hz, 1 H), 3.00 (s, 2 H), 2.78 (s, 2 H), 2.67 (t, J=7.32 Hz, 2 H), 2.01 (d, J=2.44 Hz, 1 H), 1.92 (s, 1 H), 1.59 (d, J=5.80 Hz, 2 H), 1.46 (s, 1 H). MS (LC/MS) R.T.=1.44; [M+H]+=316.16.