Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[C:60]([O:66][CH3:67])[C:20]=1[CH:21]=[CH:22][CH:23]([S:33]([CH:36]([CH:46]=[CH:47][C:48]1[C:53]([O:54][CH3:55])=[CH:52][C:51]([O:56][CH3:57])=[CH:50][C:49]=1[O:58][CH3:59])[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([NH2:45])[CH:38]=1)(=[O:35])=[O:34])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([NH2:32])[CH:25]=1>O1CCCC1>[CH3:67][O:66][C:60]1[CH:61]=[C:62]([O:64][CH3:65])[CH:63]=[C:19]([O:18][CH3:17])[C:20]=1/[CH:21]=[CH:22]/[CH:23]([S:33]([CH:36](/[CH:46]=[CH:47]/[C:48]1[C:49]([O:58][CH3:59])=[CH:50][C:51]([O:56][CH3:57])=[CH:52][C:53]=1[O:54][CH3:55])[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([NH:45][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:16][CH:15]=2)[CH:38]=1)(=[O:35])=[O:34])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([NH:32][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[CH:25]=1
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3ccc(N4CCN(C)CC4)cc3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3ccc(N4CCN(C)CC4)cc3)c2)c(OC)c1
Reaction time: 8 h

Procedure:
To a solution of 4-(4-methylpiperazin-1-yl)benzoyl chloride (10 mmol) in tetrahydrofuran (40 mL) is added dropwise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in tetrahydrofuran. The solution is stirred overnight and the reaction progress is monitored by TLC. The solvent is removed and the residue is taken up in dichloromethane and washed with water. The organic layer is dried over anhydrous sodium sulfate and evaporated to give the desired amide product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)[N:5]=[C:4]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)[N:5]=[C:4]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1cccc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCCC2)nc1-c1cccc2ncccc12
Yield: 93.3 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-2-(piperidin-1-yl)-6-(quinolin-5-yl)pyrimidin-5-yl)pentanoate (0.070 g; 0.167 mmol), sodium hydroxide 10N (0.200 mL; 2.00 mmol) in methanol (2 mL) at 60° C. for 18 h to afford 0.063 g (88%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:10]1.C1C(=O)N([Br:35])C(=O)C1>>[Br:35][CH2:20][C:13]1[NH:12][C:11]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(c2ncccc2F)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2ncccc2F)=NC1c1ccc(Cl)cc1Cl
Yield: 65 %

Procedure:
Ethyl 4-(2,4-dichlorophenyl)-2-(3-fluoropyridin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (3.14 g, 7.7 mmol) was reacted with NBS (1.51 g, 8.47 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (2.44 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([N:3]([CH3:32])[C:4]1[N:5]=[C:6]([NH:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=2)[C:7]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:11]=[C:10]([C:21]([OH:23])=O)[C:8]=2[N:9]=1)[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47]>CN(C)C1C=CN=CC=1.ClCCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([N:3]([CH3:32])[C:4]1[N:5]=[C:6]([NH:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=2)[C:7]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][C:17]([F:18])([F:19])[F:20])[N:11]=[C:10]([C:21]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:23])[C:8]=2[N:9]=1)[CH3:2]
Reactant: CS(N)(=O)=O
Reactant: CCN(C)c1nc(Nc2cc(C)ccn2)c2c(n1)c(C(=O)O)nn2CCOCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(C)c1nc(Nc2cc(C)ccn2)c2c(n1)c(C(=O)NS(C)(=O)=O)nn2CCOCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the chloride from preparation 261 (50 mg, 0.1 mmol), N-ethyldiisopropylamine (0.05 mL, 0.3 mmol), N-ethylmethylamine (0.026 mL, 0.3 mmol) and cesium fluoride (15 mg, 0.1 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was heated in a Reactivial® at 110° C. for 90 minutes. The cooled reaction mixture was purified directly using a Phenomenex Luna C18 column reverse phase column and acetonitrile:95% water/5% methanol/0.1% trifluoroacetic acid (5:95 to 95:5) as elution gradient. The product was dissolved in dichloromethane and the solution washed with sodium bicarbonate solution, dried over magnesium sulphate and evaporated under reduced pressure to provide the title compound, 24 mg. Alternatively, example 178 may be prepared by the method of examples 172-177. 4-Dimethylaminopyridine (22 mg, 0.20 mmol) was added to a solution of the acid from example 127 (70 mg, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0.20 mmol) and methanesulphonamide (19 mg, 0.20 mmol) in dichloromethane (2 ml) and the reaction stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (20 mls) and 1M citric acid solution (10 ml), then the phases separated. The organic phase was purified directly by column chromatography on silica gel (using a Parallel Flashmaster system) using an elution gradient of methanol:dichloromethane (0:100 to 2:98) to provide the title compound as a yellow solid. 1H NMR (DMSO-D6+1 drop TFAd, 400 MHz) δ: 1.19 (t, 3H), 2.49 (s, 3H), 3.20 (s, 3H), 3.41 (s, 3H), 3.66 (q, 2H), 4.06 (q, 2H), 4.14 (t, 2H), 5.03 (t, 2H), 7.20 (d, 1H), 8.12 (s, 1H), 8.27 (d, 1H). MS ES− m/z 529 [M-H]−
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][C@@H:5]2[CH:7]=[CH:8][C@@H:9]([C@H:10]3[CH2:12][O:11]3)[C@@H:4]2[O:3]1.[NH3:14]>CO>[NH2:14][CH2:12][C@H:10]([C@H:9]1[C@H:4]2[C@H:5]([O:6][C:2]([CH3:13])([CH3:1])[O:3]2)[CH:7]=[CH:8]1)[OH:11]
Reactant: N
Reactant: CC1(C)O[C@H]2[C@H]([C@H]3CO3)C=C[C@H]2O1
Solvent: CO
Product: CC1(C)O[C@H]2[C@H]([C@H](O)CN)C=C[C@H]2O1
Temperature: 100 °C

Procedure:
(3aS,4S,6aR)-2,2-dimethyl-4-((S)-oxiran-2-yl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole (2-4) (3 g, 16.5 mmol, 1.0 equiv) was dissolved in a solution of ammonia in methanol (200 mL, 7 N). The mixture was heated in the microwave at 100° C. for 30 minutes. The reaction was concentrated to afford desired (S)-2-amino-1-((3aS,4S,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (2-5) as an amber oil that was carried to the next step without further purification. 1NMR (500 MHz, CDCl3): δ 5.98-5.86 (m, 1H); 5.91-5.65 (m, 1H); 5.13 (s, 1H); 4.80-4.45 (m, 1H); 3.03 (s, 1H); 2.95-2.83 (m, 2H); 2.74 (s, 2H); 2.61 (s, 2H); 1.41 (s, 3H); 1.35 (s, 3H).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[K+]>O>[NH2:10][C:8](=[N:9][C:12](=[O:13])[O:14][CH3:15])[S:7][CH3:6]
Reactant: CSC(=N)N
Reactant: COC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N=C(N)SC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 69.5 parts of 2-methyl-2-thio-pseudourea sulfate and 47 parts of methyl chloroformate in 1000 parts of water at 0° is added dropwise, 56.9 parts of potassium hydroxide in 200 parts of water. The reaction mixture is stirred at room temperature for 3 hours and then extracted with methylene chloride. The methylene chloride extract is dried and the solvent evaporated on a rotary evaporator to give 45 parts of methyl N-(1-amino-1-methylthiomethylene)carbamate, m.p. 72°-77°.
Reaction SMILES: C(C1C(C[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=C2N=C(C)C=C(C)N2N=1)C.C([Mg]Br)=C.CCOCC.[CH3:31][C@H:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.O>[CH3:15][C@H:16]1[CH2:17][C:18](=[O:21])[CH2:19][CH2:20][N:39]1[C@H:32]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:31]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(O)cc1
Reactant: C[C@H](N)c1ccccc1
Agent: C=C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C[C@H]1CC(=O)CCN1[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried roundbottomflask (E)-but-2-enoic acid methoxy-methyl-amide (Einhorn et al., Synth. Commun. 20 (8), 1105-1112 (1990)) (8.0 g, 61.9 mmol) was dissolved in 150 ml of THF. A 1M solution of vinylmagnesium bromide in Et2O (68.1 ml, 68.1 mmol) was added at 0° C. and then the mixture was stirred for 1 h at rt. (S)-(−)-alpha-methylbenzylamin (15.8 ml, 124 mmol) was added at rt, followed by water (15 ml). The reaction was stirred at rt for 1 h. THF was evaporated and 150 ml of water was added. Then the mixture was extracted three times with CH2Cl2 The organic layer was washed with brine, dried over Na2 SO4 and evaporated. The crude product was purified by flash chromatography (silica gel, 20% EtOAc/cyclohexane) which furnished the (S,S) product as the first fraction (confirmed by x-ray).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][N:5]([C:8]1[C:9]2[CH:17]([CH3:18])[C:16](=O)[N:15]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[C:10]=2[N:11]=[C:12]([CH3:14])[N:13]=1)[CH2:6][CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:4]([N:5]([C:8]1[C:9]2[CH:17]([CH3:18])[CH2:16][N:15]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[C:10]=2[N:11]=[C:12]([CH3:14])[N:13]=1)[CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1]
Reactant: CCCCN(CC)c1nc(C)nc2c1C(C)C(=O)N2c1c(C)cc(C)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCN(CC)c1nc(C)nc2c1C(C)CN2c1c(C)cc(C)cc1C

Procedure:
A solution of (4-butyl-ethyl-amino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one) (111 mg, 0.292 mmol) in dry THF was treated with lithium aluminum hydride at room temperature. The resulting mixture was heated at reflux for 5 hours. After standard work-up, 97 mg of crude material as an oil was obtained. The oil was purified through a chromatotron using 10% ethyl acetate in hexane as eluent to give butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethylamine as a clear pale yellow oil. 1H NMR (CDCl3) δ6.91 (d, 2H), 3.7-3.9 (m, 2H), 3.2-3.4 (m, 4H), 2.5 (q, 1H), 2.28 (s, 6H), 2.22 (s, 3H), 2.05 (s, 3H), 1.5-1.7 (m, 2H), 1.3-1.5 (m, 5H), 1.17 (t, 3H), 0.97 (t, 3H) ppm. High MS (C23H34N4) calc. 366.2776, found 366.27622.
Reaction SMILES: CS(O[CH2:6][C:7]([O:19][CH3:20])([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])[CH2:8][CH2:9][CH3:10])(=O)=O.[Na].[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1>CS(C)=O>[N:22]1([CH2:6][C:7]([O:19][CH3:20])([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH2:8][CH2:9][CH3:10])[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: c1nc[nH]n1
Reactant: CCCC(COS(C)(=O)=O)(OC)c1ccc(Cl)cc1Cl
Agent: [Na]
Solvent: CS(C)=O
Product: CCCC(Cn1cncn1)(OC)c1ccc(Cl)cc1Cl
Temperature: 120 °C
Reaction time: 16 h

Procedure:
The crude product prepared in (a) is dissolved in 50 ml of absolute dimethyl sulfoxide, and 2.2 g (24 mmoles) of the sodium salt of 1,2,4-triazole are added. The reaction mixture is stirred for 16 hours at a bath temperature of 120° C. The resulting dark solution is cooled to room temperature, poured into ice water and extracted twice with ethyl acetate. The combined extracts are washed four times with half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified by colum chromatography (silica gel; 1:1 ethyl acetate/petroleum ether) and affords 3.2 g (=64% of theory) of a colourless oil. Boiling point 170°-175° C./0.04 mbar. 60 MHz-1H-NMR (CDCl3): δ=7.75 and 7.60 ppm (2s, 2H of the triazole); 6.9-7.5 ppm (m, 3H, aromatic); 4.8 ppm (4 lines AB spectrum, 2H, CH2N); 3.4 ppm (s, 3H, OCH3); 1.7-2.5 ##STR35## 0.7-1.5 ppm (m, 5H, CH2CH3).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[CH3:13][C:14]([O-:16])=[O:15].[Na+]>CC(O)=O>[C:14]([O:16][CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6])(=[O:15])[CH3:13]
Reactant: N#Cc1c(Cl)cc(Cl)cc1CBr
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1cc(Cl)cc(Cl)c1C#N
Temperature: 100 °C

Procedure:
To a solution of 2-(bromomethyl)-4,6-dichlorobenzonitrile (15.1 mmol) in 30 mL AcOH was added NaOAc (75.7 mmol). The suspension was heated to 100° C. for 2 h. The solvent was evaporated off and the residue partitioned between DCM and water. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept/EtOAc (95/5 to 30/70) gives the desired compound as white solid.
Reaction SMILES: [NH:1]([C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[C@H:2]([C:20]([NH:22][C@H:23]([C:41]([N:43]1[CH2:82][CH2:81][CH2:80][C@H:44]1[C:45]([NH:47][C@H:48]([C:50]([NH:52][C@H:53]([C:70]([O:72]CC1C=CC=CC=1)=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][NH:58][C:59]([O:61][CH2:62][C:63]1[CH:69]=[CH:68][CH:67]=[CH:66][C:64]=1[Cl:65])=[O:60])=[O:51])[CH3:49])=[O:46])=[O:42])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:40])[NH:29][S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:83]([O:85][C:86]([CH3:87])([CH3:89])[CH3:88])=[O:84])[C@H:2]([C:20]([NH:22][C@H:23]([C:41]([N:43]1[CH2:82][CH2:81][CH2:80][C@H:44]1[C:45]([NH:47][C@H:48]([C:50]([NH:52][C@H:53]([C:70]([OH:72])=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][NH:58][C:59]([O:61][CH2:62][C:63]1[CH:69]=[CH:68][CH:67]=[CH:66][C:64]=1[Cl:65])=[O:60])=[O:51])[CH3:49])=[O:46])=[O:42])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:40])[NH:29][S:30]([C:33]1[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=1)(=[O:32])=[O:31])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:10])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)NS(=O)(=O)c2ccc(C)cc2)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)NS(=O)(=O)c2ccc(C)cc2)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
At 0° C. to the solution of 600 mg (0.464 mmol) of Boc-Arg(Tos)-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 18) in 10 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Arg(Tos)-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 18). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 420 mg (76%) of the title compound as a colorless powder.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([CH:31]([F:33])[F:32])=[N:11][CH:12]=[C:13]([C:15]2[N:20]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:19]3[C:18](Cl)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][NH2:41]>>[C:1]([NH:5][S:6]([C:9]1[C:10]([CH:31]([F:33])[F:32])=[N:11][CH:12]=[C:13]([C:15]2[N:20]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:19]3[C:18]([NH:41][CH2:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccn1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(-c2nnc(Cl)c3c(-c4ccccc4)ccn23)cnc1C(F)F
Product: CC(C)(C)NS(=O)(=O)c1cc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)ccn23)cnc1C(F)F
Yield: 62.1 %

Procedure:
A solution of N-(tert-butyl)-5-(1-chloro-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)-2-(difluoromethyl)pyridine-3-sulfonamide (0.050 g, 0.10 mmol) in pyridin-2-ylmethanamine (0.110 g, 1.02 mmol) was heated in a sealed tube at 100° C. for 6 h. The volatile components were removed under reduced pressure and the resulting residue was purified by CombiFlash Isco (REDISEP®, SiO2, 24 g, 0-60% EtOAc/petroleum ether) to obtain N-(tert-butyl)-2-(difluoromethyl)-5-(8-phenyl-1-((pyridin-2-ylmethyl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (0.035 g, 61%) as a brown solid. LCMS Method B-4: retention time 1.12 min, [M+1]=564.5. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.18 (s, 9H), 4.63 (d, J=6.0 Hz, 2H), 6.61 (dd, J=4.4 Hz, J=6.0 Hz, 1H), 6.98 (d, J=2.8 Hz, 1H), 7.33-7.70 (m, 8H), 7.72 (d, J=2.8 Hz, 1H), 7.98-8.05 (m, 1H), 8.32 (d, J=4.8 Hz, 1H), 8.35 (s, 1H), 8.80 (br s, 1H), 9.41 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]#[C:4][CH2:5][CH2:6][O:7][C:8]1[N:13]=[CH:12][CH:11]=CN=1>[N+](C1C=CC=CC=1)([O-])=O>[CH3:15][Si:2]([CH3:1])([CH3:14])[C:3]1[CH:11]=[CH:12][N:13]=[C:8]2[O:7][CH2:6][CH2:5][C:4]=12
Reactant: C[Si](C)(C)C#CCCOc1ncccn1
Solvent: O=[N+]([O-])c1ccccc1
Product: C[Si](C)(C)c1ccnc2c1CCO2
Yield: 16 %

Procedure:
A solution of 2-{[4-(trimethylsilyl)but-3-yn-1-yl]oxy}pyrimidine (116 g, 524 mmol) in nitrobenzene (1000 mL) was stirred at 200° C. for 24 hr. The solvent was removed by silica gel column chromatography (ethyl acetate/hexane=13/87→50/50). The residue was diluted with ethyl acetate, and the mixture was extracted twice with 1M hydrochloric acid. The aqueous layer was neutralized with 8M aqueous sodium hydroxide solution and extracted with ethyl acetate. The solvent was evaporated under reduced pressure to give the title compound (16.2 g, yield 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH:32]([OH:33])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCC(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCC(O)c3ccccc3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 2-amino-1-phenylethanol (27 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-[(2-hydroxy-2-phenylethyl)aminomethyl]indol-2-yl]isoindolinone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][C:45](Cl)=[O:46]>>[N:34]1([CH2:33][CH2:32][CH2:31][O:30][C:26]2[CH:25]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:45](=[O:46])[CH2:44][C:40]6[S:39][CH:43]=[CH:42][CH:41]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCN4CCCC4)c3)n2)c1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCN4CCCC4)c3)n2)c1
Yield: 51 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[3-(1-pyrrolidinyl)propyl]oxy}phenyl)-2-pyrimidinamine using acylation with 2-thienylacetyl chloride as described in Example 10, Step E to yield a light brown solid in 51% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.6 (s, 4H) 1.8 (s, 2H) 2.4 (s, 4H) 3.9 (s, 2H) 3.9 (d, J=6.2 Hz, 2H) 6.5 (m, 2H) 7.0 (m, 2H) 7.1 (m, 2H) 7.3 (ddd, J=6.3, 1.3, 1.2 Hz, 2H) 7.4 (m, 3H) 7.5 (t, J=2.3 Hz, 1H) 7.7 (m, 1H) 7.9 (d, J=1.8 Hz, 1H) 8.2 (d, J=5.1 Hz, 1H) 8.5 (s, 1H) 8.8 (m, 1H) 9.5 (s, 1H) 10.3 (s, 1H). ES-LC/MS m/z 630 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[H-].[Na+].[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[S:23](Cl)(=[O:25])=[O:24]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:7][S:23]([C:15]2[O:14][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=2)(=[O:24])=[O:25])[CH:8]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 378 %

Procedure:
To a −10° C. cold yellow solution of 5-chloro-2-nitroaniline (8.00 g, 46.36 mmol) in dry DMF (130 ml) was added sodium hydride 60% (9.27 g, 231.79 mmol) under Ar. The resulting red suspension was stirred at −10° C. for 10 minutes. A solution of 1-benzofuran-2-sulfonyl chloride (12.05 g, 55.63 mmol) in dry DMF (50 ml) was added dropwise with a dropping funnel at −10° C. (10 minutes of addition, exothermic reaction, maximum temperature of addition was 0° C., 5 ml of DMF to rinse the funnel). The resulting orange suspension was stirred at −10° C. for 30 minutes (color changed to brown). The reaction mixture was quenched with half saturated NaHCO3 solution (400 ml) and the product was extracted five times with EtOAc (1×650 ml and 4×300 ml). The combined organic layers were dried over Na2SO4, filtered and the filtrate evaporated to dryness. The crude product was combined with the crude product of an analogously performed 8 g scale attempt to give 61.82 g of an orange oil which was purified by MPLC (crude was dissolved in CH2Cl2/MeOH, preabsorption on silica gel, column D, program 3, 5 runs) to afford Intermediate 4 (28.91 g, 88% yield based on combined starting material) as yellow solid.