Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[CH:16]=[CH:15][N:14]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.CCOCC>[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[CH:16]=[C:15]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[N:14]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Clc1ccsc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Clc1cc(-c2sccc2Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-chlorothiophene (384 mg, 3.0 mmol) in THF (6 mL) at −78° C. was added n-BuLi (1.6 M, 2 mL) and the resulting mixture stirred for 45 minutes. The resulting product was added to a solution of 2,4-dichloropyrimidine (430 mg, 2.9 mmol) in ether (10 mL) at −30° C. and the resulting mixture stirred for 30 minutes, then warmed up to 0° C. and stirred for another 30 minutes. DDQ (700 mg, 3 mmol) was added and the resulting mixture was stirred overnight, then filtered through Celite®. The filtrate was concentrated and the residue was purified by silica gel column (EtOAc/hexanes, 1:5) to yield a white solid.
Reaction SMILES: C([C:3]1[C:4]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[N:5][CH:6]=[C:7]([CH:9]([Cl:11])[Cl:10])[N:8]=1)=O.Cl.[NH2:24][OH:25].O>CS(C)=O>[N:24](=[C:3]1[N:8]=[C:7]([CH:9]([Cl:11])[Cl:10])[CH:6]=[N:5][CH:4]1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[OH:25]
Reactant: NO
Reactant: O=Cc1nc(C(Cl)Cl)cnc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1N=CC(C(Cl)Cl)=NC1=NO
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
A solution of 10 g of 3-formyl-5-dichloromethyl-2-phthalimidopyrazine in 50 ml of dimethyl sulfoxide was heated at 50° C., 7 g of hydroxylamine hydrochloride were added, and the mixture was stirred for 15 minutes at 70° C. Thereafter, 700 ml of water were added to the reaction solution, the mixture was filtered and the filtrate was washed with a little diethyl ether. 6.8 g of colorless crystals (65%) of 3-oximinodichloromethyl-2-phthalimidopyrazine were obtained. 1H-NMR (270 MHz, DMSO-d6): δ7.7 (s, 1H), 8.0 (m, 4H), 8.3 (s, 1HO), 9.1 (s, 1H), 12.0 (s, OH).
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[N:19]([CH:29]1[CH2:32][N:31]([S:33]([OH:36])(=[O:35])=[O:34])[C:30]1=[O:37])[C:20](=[O:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[K].C([N+](CCCC)(CCCC)CCCC)CCC.O=C1C(N(Cl)C([O:64][CH2:65][C:66]2C=CC=[CH:68][CH:67]=2)=O)CN1S([O-])(=O)=O>>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[CH2:65]([O:64][C:29]1([NH:19][C:20](=[O:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:32][N:31]([S:33]([OH:36])(=[O:35])=[O:34])[C:30]1=[O:37])[CH2:66][CH2:67][CH3:68]
Reactant: O=C(Cc1ccccc1)N(Cl)C1CN(S(=O)(=O)O)C1=O
Reactant: O=C(OCc1ccccc1)N(Cl)C1CN(S(=O)(=O)[O-])C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K]
Product: CCCCOC1(NC(=O)Cc2ccccc2)CN(S(=O)(=O)O)C1=O

Procedure:
Following the procedure of Example 80, but substituting N-chloro-N-(2-oxo-1-sulfo-3-azetidinyl)-2-phenylacetamide, tetrabutylammonium salt (see Example 47A for preparation of the corresponding potassium salt) for 2-oxo-3-[N-chloro-N-[(phenylmethoxy)carbonyl]amino]-1-azetidinesulfonic acid, tetrabutylammonium salt, yields the title compound as an oil: nmr (CDCl3) 3.62 (s,2H,C6H5CH2), 4.03 (ABq,2H,ν=7 cps, C-4 CH2), 6.98 (s,1H,NH) and 7.30 ppm (S,5H,C6H5).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:9]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)=O.N1CCCCC1>C(O)C>[C:1](/[C:3](=[CH:9]/[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)/C(C#N)=C\c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl cyanoacetate (2.59 g, 22.88 mmol) and 4-formylbenzonitrile (3.0 g, 22.88 mmol) are dissolved in ethanol (100 ml). Piperidine (100 mg, 1.14 mmol) is added, and the reaction mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo, and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:22][CH2:21][C:16]4(OCC[O:17]4)[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>CC(C)=O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(C3=CCC4(CC3)OCCO4)c[nH]c2c1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reaction time: 14 h
Yield: 84.4 %

Procedure:
A solution of compound 118 (3.9 g, 12.986 mmol) in acetone (50 mL) was treated with 10% aq. HCl (50 mL) at room temperature and stirred for over night (14 h). Solvent was evaporated and crude was basified using 10% aq. NH4OH solution (100 mL). The solid was filtered off, washed with 10% NH4OH solution (20 mL), water (2×15 mL) and dried under vacuum to obtain compound 119 (2.81 g, 85%) as a yellow solid. mp 175-177° C.; 1H NMR (DMSO-d6) δ 2.58 (t, 2H, J=6.9 Hz), 2.90 (t, 2H, J=6.9 Hz), 3.04-3.10 (m, 2H), 6.24 (t, 1H, J=3.9 Hz), 7.90-8.01 (m, 3H), 8.33 (d, 1H, J=2.1 Hz), 11.95 (s, 1H); ESI-MS (m/z, %): 279 (M+Na, 100), 257 (MH+, 33).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=O)[CH2:9][CH2:8]2.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)[CH2:9][CH2:8]2
Reactant: CN1CCNCC1
Reactant: COc1cccc2c1CC(=O)CC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc2c1CC(N1CCN(C)CC1)CC2
Reaction time: 0.5 h
Yield: 161.3 %

Procedure:
1.76 g (10 mmol) of 8-methoxy-2-tetralone, 3.00 g (30 mmol) of N-methylpiperazine and 1.80 g (30 mmol) of glacial acetic acid were refluxed in 30 ml of methanol for 4 hours. 1.30 g (20 mmol) of sodium cyanoborohydride were then added, and the mixture was refluxed for a further hour. The reaction mixture was substantially concentrated in a rotary evaporator, taken up in tert.-butyl methyl ether, and stirred vigorously for 30 minutes in 20% strength sodium hydroxide solution. The aqueous phase was extracted carefully with tert.-butyl methyl ether. Washing the combined organic phases with water and saturated sodium chloride solution, drying over potassium carbonate, and concentrating in a rotary evaporator yielded the crude product as an oil (2.9 g). This crude product was combined with that obtained from a batch of equal size (this reaction was carried out in the presence of 3A molecular sieve, otherwise the same) and chromatographed on silica gel (toluene/methanol 4:1). 4.20 g of the title compound were obtained in this fashion as a brownish oil (80%).
Reaction SMILES: ClCCC[O:5][P:6]1[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1.[CH2:12](O)[CH2:13][OH:14].C(Br)C>ClCCCl>[OH:14][CH2:13][CH2:12][P:6]1(=[O:5])[CH2:10][CH2:9][C:8]([CH3:11])=[CH:7]1
Reactant: CC1=CCP(OCCCCl)C1
Reactant: OCCO
Solvent: CCBr
Solvent: ClCCCl
Product: CC1=CP(=O)(CCO)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 14.7 g. (0.076 mole) of 1-(chloropropoxy)-3-methyl-3-phospholene in 50 ml. of 1,2-dichloroethane was added, with stirring, over a period of 5 minutes, a total of 14.14 g. (0.23 mole) of ethylene glycol. The resulting solution was cloudy. Ethyl bromide (1.66 g.) was added and the mixture was heated under reflux for 1 hour. At the end of this time the solvent and other volatile materials were removed by evaporation and the residue was distilled under reduced pressure. There was thus obtained 1.3 g. (10.6% theoretical yield) of a mixture of the 2- and 3-isomers of 1-(2-hydroxyethyl)-3-methylphospholene-1-oxide in the form of a liquid having a boiling point of 125° - 150° C at 0.2 mm. of mercury. A glassy residue remained in the distillation flask and was believed to be 1,1'-ethylenebis-(3-methylphospholene-1-oxide).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[C:15]([Cl:26])[C:14]=2[N+:27]([O-:29])=[O:28])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:30](Cl)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([N:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=1)[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[C:15]([Cl:26])[C:14]=1[N+:27]([O-:29])=[O:28])(=[O:32])[CH3:31]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Nc1ncc(C(F)(F)F)cc1Cl
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)N(c1ncc(C(F)(F)F)cc1Cl)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]

Procedure:
In 20 ml. of pyridine, 2.3 g. of N-(3-chloro-5-trifluoromethyl-2-pyridyl)-2,6-dinitro-3-chloro-4-trifluoromethylaniline (obtained in Preparation 4) was dissolved and a solution of 0.34 g. of acetylchloride in 10 ml. of pyridine was added dropwise to react them at 60° to 70° C. for 2 hours. Pyridine was distilled off from the reaction mixture and the product was separated by a silica gel column with an eluent of n-hexane and ethyl acetate (4:1) and the solvent was distilled off to obtain 0.8 g. of the object compound having the melting point of 75° to 77° C.
Reaction SMILES: [CH:1]1([C:7](N(C2C=CC=CC=2OC(F)(F)F)CCN2CCN(C3C=CC([N+]([O-])=O)=CC=3OC)CC2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:40][C:41]([F:69])([F:68])[O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][N:55]([CH2:58][C:59]2[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=2[Br:67])[CH2:54][CH2:53]1>>[CH:1]1([C:7]([N:49]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][C:41]([F:40])([F:68])[F:69])[CH2:50][CH2:51][N:52]2[CH2:57][CH2:56][N:55]([CH2:58][C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[Br:67])[CH2:54][CH2:53]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2OC(F)(F)F)CC1
Reactant: COc1ccc(Br)c(CN2CCN(CCNc3ccccc3OC(F)(F)F)CC2)c1
Product: COc1ccc(Br)c(CN2CCN(CCN(C(=O)C3CCCCC3)c3ccccc3OC(F)(F)F)CC2)c1
Yield: 67 %

Procedure:
The title compound was prepared following the procedure described for the compound of example 55, substituting the compound of example 74 for the compound of example 54. The residue was purified by flash chromatography (CHCl3-2 N methanolic NH3 100:1). Yield: 67%.
Reaction SMILES: [O:1]=[C:2]1[C:7]2=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10][N:6]2[N:5]=[C:4]([C@@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])[N:3]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.FC(F)(F)C(O)=O>>[NH2:20][C@H:18]([C:4]1[N:3]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:2](=[O:1])[C:7]2=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10][N:6]2[N:5]=1)[CH3:19]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(Sc3ccccc3)c2c(=O)n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nn2ccc(Sc3ccccc3)c2c(=O)n1-c1ccccc1
Yield: 95.6 %

Procedure:
(S)-tert-Butyl (1-(4-oxo-3-phenyl-5-(phenylthio)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (190 mg, 0.41 mmol) was treated with trifluoroacetic acid (316 μl, 4.10 mmol) according to the method of Preparation 6 to obtain 142 mg (95% yield) of the title compound as a oil. Purity 95%.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([O:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH2:32])[CH2:11][O:12][CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])(C(C)(C)C)(C)C>C(O)(=O)C>[CH2:17]([O:16][P:14]([CH2:13][O:12][CH2:11][CH:10]([O:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH2:32])[CH2:9][OH:8])([O:19][CH2:20][CH3:21])=[O:15])[CH3:18]
Reactant: CCOP(=O)(COCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(N)ncnc21)OCC
Solvent: CC(=O)O
Product: CCOP(=O)(COCC(CO)On1cnc2c(N)ncnc21)OCC

Procedure:
A solution of 9-(1-t-butyldimethylsilyloxy-3-diethoxyphosphorylmethoxyprop-2-oxy)adenine (170 mg, 0.35 mmol) in 80% aqueous acetic acid (5 ml) was stirred at 85° C. for 5 hours. After evaporation, the residue was chromatographed on silica eluting with ethyl acetate-methanol 5:1 affording 9-(1-diethoxyphosphorylmethoxy3-hydroxyprop-2-oxy)adenine (120 mg, 92%) as a clear gum. νmax (film) 3340; 1700, 1600, 1330, 1290, 1240, 1030 and 970 cm-1 ; δH (CDCl3) 1.38(6H, t, J7.1 Hz, 2×CH2CH3), 3.70(2H, m, CH2OH), 3.89(4H, m, CH2OCH2P), 4.22(4H, m, 2×CH2CH3), 4.50(1H, m, CHON), 5.63(1H, m, D2O exchangeable, OH), 5.89(2H, br.s, D2O exchangeable, NH2), 8.18(1H, s, H-2/H-8), 8.34(1H, s, H-2/H-8); Found: C,39.58; H,5.69; N,17.69%; M+ 375.1317; C13H22N5O6P.0.9H2O requires C,39.87; H,6.08; N,17.89%; M+ 375.1308.
Reaction SMILES: [N:1]([C:4]([CH3:7])([CH3:6])[CH3:5])=[C:2]=[S:3].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[C:4]([NH:1][C:2]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1)=[S:3])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C)(C)N=C=S
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=S)NC(C)(C)C)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 2-isothiocyanato-2-methylpropane and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 419.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][OH:32].C(=O)([O-])O.[Na+]>C1COCC1>[OH:32][CH2:31][CH2:30][N:29]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1)[CH2:33][CH2:34][OH:35]
Reactant: OCCNCCO
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(CCO)CCO)cc2)CC3)cc1
Temperature: 25 °C

Procedure:
In THF (10ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (300mg), and to the mixture was added diethanolamine (222 μl). The mixture was refluxed for 34 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/triethylamine=10/1) and recrystallized from ethyl acetate-hexane to give N-[4-[N,N-bis(2-hydroxyethyl)-aminomethyl]phenyl]-7-(4-methylphenyl)-3,4-dihydro-naphthalene-2-carboxamide (Compound 51) (148mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15](S(C3C=CC(C)=CC=3)(=O)=O)[CH:14]=2)[N:10]=[CH:9][C:8]=1[CH2:32][C:33]([NH2:35])=[O:34].Cl>CO.[OH-].[Na+].O>[F:39][C:37]1[CH:36]=[C:4]([CH:3]=[C:2]([F:1])[CH:38]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[N:10]=[CH:9][C:8]=1[CH2:32][C:33]([NH2:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)c3cccnc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)Cc1cnc(-c2c[nH]c3ncccc23)cc1NCc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.4 %

Procedure:
10 mg of 4-[(3,5-difluorobenzyl)amino]-6-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}pyridine-3-carboxyamide (the compound of Example 370) was dissolved in 0.5 mL of methanol, to which 0.5 mL of 6 mol/L sodium hydroxide in water was added, and stirred at room temperature for 4 hours. Under ice cooling, hydrochloric acid was added to acidify (about pH 1) the reaction mixture, and washed with chloroform. The aqueous layer was basified (about pH 8) with saturated sodium bicarbonate in water, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 2.9 mg (yield 41%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]([CH2:35]Cl)=[CH2:34]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:35][C:33]([Cl:32])=[CH2:34])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: C=C(Cl)CCl
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(Cl)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)OCCCC)nn1
Temperature: 25 °C
Yield: 72 %

Procedure:
Butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxy late (reference example 11) (0.28 g, 0.69 mmol) in DMF (4 ml) was treated with potassium carbonate (0.28 g, 2.05 mmol) followed by 2,3-dichloro-1-propene (168 mg, 140 μl, 1.4 mmol) and the mixture stirred at ambient temperature over the weekend. The mixture was evaporated, in vacuo, to dryness, presorbed to 1.5 g silica and purified by MPLC to give the title compound as a colourless gum (0.24 g, 72%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: Nc1cccc(O)c1
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1Cl
Product: COc1ccc(Nc2nc(Nc3cccc(O)c3)ncc2F)cc1Cl

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 3-hydroxyaniline were reacted to produce N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.91 (d, 1H, J=5.4 Hz), 7.71 (d, 1H, J=2.4 Hz), 7.58 (dd, 1H, J=3.0 and 9.0 Hz), 7.15 (t, 1H, J=8.4 Hz), 7.06 (d, 1H, J=8.7 Hz), 6.92 (td, 1H, J=1.8 and 9.9 Hz), 6.88 (t, 1H, J=1.8 Hz), 6.61 (ddd, 1H, J=1.2, 2.4, and 8.1 Hz), 3.89 (s, 3H),; 19F NMR (282 MHz, CD3OD): −46612; LCMS: purity: 98%; MS (m/e): 362(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:36][CH2:37][O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=O)=O>>[Si:39]([O:38][CH2:37][CH2:36][CH:16]([N:11]1[CH:12]=[C:13]([O:14][CH3:15])[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:28]#[N:29])=[CH:9][C:10]1=[O:27])[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])([C:52]([CH3:53])([CH3:54])[CH3:55])([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1cn(CC(=O)OCc2ccccc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)[Si](OCCOS(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Product: COc1cn(C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)OCc2ccccc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.00 g (2.45 mmol) of benzyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 2.69 ml (2.69 mmol, 1.1 eq.) of bis(trimethylsilyl)lithium amide (1M in tetrahydrofuran) and 1.59 g (3.67 mmol, 1.5 eq.) of 2-{[tert-butyl(diphenyl)silyl]oxy}ethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 708 mg (40% of theory)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([O-:26])=[O:25]>C(Cl)Cl>[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:32][CH:31]=2)(=[O:34])=[O:35])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Diisopropylethylamine (4.5 ml, 27.0 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (5.0 g, 20.0 mmol) in DCM (40 ml) at room temperature. To this mixture was added 4-nitrophenyl sulfonyl chloride (6.0 g, 27.0 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting solid was collected by filtration, dried with diethyl ether and dried under vacuum give the title compound (7.14 g, 74% yield) as a pale yellow solid. Tr=2.07 min m/z (ES+) (M+Na+) 408.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:25]([Cu])#[N:26]>CN(C=O)C>[C:25]([C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])#[N:26]
Reactant: CC1(C)CCN(c2ccc(CNC(=O)OC(C)(C)C)cc2Br)CC1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CC1(C)CCN(c2ccc(CNC(=O)OC(C)(C)C)cc2C#N)CC1
Temperature: 140 °C
Yield: 44.8 %

Procedure:
In a screw cap pressure tube were tert-butyl 3-bromo-4-(4,4-dimethylpiperidin-1-yl)benzylcarbamate (105 mg, 0.26 mmol) and CuCN (47.3 mg, 0.53 mmol) suspended in DMF (1.0 ml). N2 was bubbled through the suspension for 5 min. The tube was sealed and the mixture heated to 140° C. overnight. The mixture was allowed to cool and then it was poured over ice-water. FeCl3 (94.3 mg, 0.58 mmol) was added and the product extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography (Pet. Ether/EtOAc 4:1) affording 40 mg (45%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].OS(O)(=O)=O.[BrH:16].CC(N=NC(C#N)(C)C)(C#N)C.OO>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([C:5]([Cl:8])=[CH:6][CH:7]=1)[CH2:9][Br:16]
Reactant: Cc1c(Cl)ccc(Cl)c1C
Reactant: Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: OO
Solvent: Clc1ccccc1
Product: Cc1c(Cl)ccc(Cl)c1CBr
Temperature: 70 °C
Reaction time: 5 h

Procedure:
170.1 g (0.97 mol) of 3,6-dichloro-1,2-xylene are initially charged in 1180 ml of chlorobenzene, and 4.9 g of conc. H2SO4 and 203.1 g (1.18 mol) of 47% strength hydrobromic acid are added. The mixture is heated to 70° C., and 0.9 g of AIBN are added. Over a period of 5 h, 353.7 g (1.04 mol) of a 10% strength solution of hydrogen peroxide are added at 70-75° C., the mixture is stirred at 70-75° C. for 30 min, washed twice with 400 ml of water and once with 400 ml of saturated sodium bicarbonate solution, and the chlorobenzene is then distilled off.