Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([O-:12])=[O:11].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:9]
Reactant: Oc1ccc(F)cc1Br
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc(Br)c1O
Yield: 80.9 %

Procedure:
2-Bromo-4-fluoro-phenol 2a (8.0 g, 41.9 mmol) was dissolved in 10 mL of sulfuric acid (50%) followed by addition of a solution of sodium nitrate (7.1 g, 83.5 mmol) in 24 mL of sulfuric acid (25%), upon cooling by an ice-water bath. The reaction mixture was reacted at room temperature for 1.5 hours and the reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 50 mL of water and extracted with ethyl acetate (50 mL×2). The combined organic extracts were washed with water and saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 2-bromo-4-fluoro-6-nitro-phenol 2b (8.0 g, yield 80.8%) as a red solid, which was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)[C:16](Cl)=[S:17])C>C1(C)C=CC=CC=1>[N:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:16]=[S:17]
Reactant: CCN(CC)C(=S)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(N=C=S)c1
Reaction time: 1 h
Yield: 77.3 %

Procedure:
82.5 g of ethyl m-aminobenzoate was dissolved in 500 ml of toluene and to the solution was added dropwise 83.4 g of N,N-diethylthiocarbamoyl chloride at room temperature with stirring over a period of about 1 hour. The mixture was then refluxed by heating for 5 hours. The toluene was distilled off under reduced pressure, to the residue was added 300 ml of ethyl acetate and the ethyl acetate solution was washed with water. The ethyl acetate was distilled off under reduced pressure and the residue was further subjected to vacuum distillation to obtain 80 g of ethyl m-isothiocyanatobenzoate as oily product. Boiling Point: 125° C./0.6 mm Hg. Yield: 77%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:12]([O:16][C:17]([N@@:19]1[CH2:21][CH:20]1[CH3:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([NH:19][C@H:20]([CH3:22])[CH2:21][C:4]1[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=[C:2]([F:1])[CH:3]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC1CN1C(=O)OC(C)(C)C
Reactant: Fc1cc(Br)c2occc2c1
Product: C[C@H](Cc1cc(F)cc2ccoc12)NC(=O)OC(C)(C)C
Yield: 44.3 %

Procedure:
Beginning with 5.7 gm (26.6 mMol) 5-fluoro-7-bromobenzofuran and 3.9 gm (24.8 mMol) (R)-(−)-N-tert-butoxycarbonyl-2-methylaziridine, 3.22 gm (44%) of the desired compound were prepared essentially as described in Example 10.
Reaction SMILES: C(S([N:7]=[C:8]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2)[C:9]1[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)=O)(C)(C)C.Cl.CCOCC>CO>[NH2:7][CH:8]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2)[C:9]1[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1
Reactant: CCN(CC)C(=O)c1ccc(C(=NS(=O)C(C)(C)C)c2cccc3cccnc23)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccc(C(N)c2cccc3cccnc23)cc1

Procedure:
Treatment of 15 (135 mg, ˜0.30 mmol) with HCl in ether (0.3 mL, 0.6 mmol) in MeOH (2 mL) at 25° C., for 5 min. Concentration in vacuo, dilution with water, washing with EtOAc. The solution was then made basic with K2CO3(aq), extracted with and evaporated to give (+)-6 (53 mg, 53% from 14). 1H NMR (CDCl3): δ1.2 (m, 6H), 2.2 (s, 2H), 3.4 (m, 4H), 6.40 (s, 1H), 7.30-7.58 (m, 7H), 7.71 (m, 1H), 8.15 (m, 1 H), 8.92 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C@@H:31]([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[CH3:33][N:32]1[C:25]2[N:26]([C:27](=[O:29])[N:28]=[C:23]([O:1][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([O:11][C:12]4[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=4)=[C:7]([CH:10]=3)[C:8]#[N:9])[CH:24]=2)[CH2:30][C@@H:31]1[CH3:34]
Reactant: N#Cc1cc(CO)ccc1Oc1cncc(C(F)(F)F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cncc(C(F)(F)F)c4)c(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>ClCCl>[C:16]([NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)Cl
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N[C@@H](C)C(=O)OC

Procedure:
L-Alanine methyl ester hydrochloride salt (14 g, 0.1 mol) was dissolved in dichloromethane (150 mL) and treated with triethylamine (30.45 g, 0.3 mmol). The solution was stirred and propionyl chloride added dropwise. After stirring overnight the mixture was quenched by addition of 1M hydrochloric acid (200 mL) and the organic layer separated. The aqueous layer was re-extracted with dichloromethane (3×200 mL) and the combined organic layers were dried with magnesium sulfate, filtered and evaporated to a to a clear oil (16.0 g, quant.).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:15][CH2:16][CH3:17].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:15][CH2:16][CH3:17]
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)O)cc(OCC)c1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of methyl 4-bromo-3,5-diethoxybenzoate (3.00 g) in a mixture of THF (25 ml) and MeOH (10 ml) was added aqueous 1N NaOH (20 ml) and the reaction mixture was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure and the residue was diluted with H2O and diethylether. The aqueous layer was acidified with aqueous 1N HCl, the mixture was extracted with CHCl3 and dried over sodium sulfate. After filtration and concentration, the residue was dried in vacuo to give the crude intended compound as a colorless solid. Thus obtained crude product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:20])[C@@H:12]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]1[CH2:18]C.CN1C(=O)CC[C@H]1C(O)=O.C(N1C(=O)CC[C@H]1C(O)=O)C.FC1C=CC(CN)=C([C:51]([F:54])([F:53])[F:52])C=1.ClC1C=C(F)C=CC=1CN>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][NH:10][C:11](=[O:20])[C@@H:12]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[CH3:18])=[C:2]([C:51]([F:54])([F:53])[F:52])[CH:7]=1
Reactant: NCc1ccc(F)cc1C(F)(F)F
Reactant: CCN1C(=O)CC[C@H]1C(=O)NCc1ccc(F)cc1Cl
Agent: CCN1C(=O)CC[C@H]1C(=O)O
Agent: CN1C(=O)CC[C@H]1C(=O)O
Agent: NCc1ccc(F)cc1Cl
Product: CN1C(=O)CC[C@H]1C(=O)NCc1ccc(F)cc1C(F)(F)F

Procedure:
N-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-1-methyl-5-oxoprolinamide was prepared in a manner analogous to that described above for the synthesis of N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-5-oxoprolinamide (Example 70) but 1-methyl-5-oxoproline (prepared as describe below) was substituted for 1-ethyl-5-oxoproline and {[4-fluoro-2-(trifluoromethyl)phenyl]methyl}amine was substituted for 2-chloro-4-fluorobenzylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=O)[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([O:20][CH2:21][CH3:22])[C:17]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:19])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CCOC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CCOC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
180 mg (0.50 mmol) of [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](ethoxy)acetic acid (racemate) and 105 mg (0.55 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 265 mg (quant.)
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:16])[C:7]2=[O:15].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([CH:30]2[CH2:35][CH2:34][N:33]([C:2]3[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]4[C:3]=3[CH2:4][CH2:5][N:6]([CH3:16])[C:7]4=[O:15])[CH2:32][CH2:31]2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Reactant: CN1CCc2c(F)ccc([N+](=O)[O-])c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCc2c(N3CCC(N4CCN(C(=O)OC(C)(C)C)CC4)CC3)ccc([N+](=O)[O-])c2C1=O
Temperature: 85 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
A mixture of 5-fluoro-2-methyl-8-nitro-3,4-dihydro-2H-isoquinolin-1-one (11.65 g, 0.052 mol), 4-piperidin-4-yl-piperazine-1-carboxylic acid tert-butyl ester (28.0 g, 0.1039 mol), K2CO3 (8.98 g, 0.065 mol) in DMSO (350 mL) was stirred at 85° C. for 12 hours. After cooling to room temperature, ice-water (500 mL) was added. The mixture was extracted with AcOEt. The organic layer was washed with water followed by brine, dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography (AcOEt; then AcOEt/MeOH=6/1) to give 10.09 g of the desired product 4-[1-(2-methyl-8-nitro-1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yl)-piperidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester as pale yellow solid in 41% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:18]1[C:23]([I:24])=[CH:22][N:21]=[CH:20][N:19]=1>CN(C=O)C>[F:8][C:7]1[CH:6]=[C:5]([O:9][C:18]2[C:23]([I:24])=[CH:22][N:21]=[CH:20][N:19]=2)[C:4]([F:10])=[CH:3][C:2]=1[NH2:1]
Reactant: Clc1ncncc1I
Reactant: Nc1cc(F)c(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(F)c(Oc2ncncc2I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
To a solution of 4-amino-2,5-difluorophenol (0.190 g, 1.310 mmol) in DMF (10 mL) was added potassium tert-butoxide (0.168 g, 1.497 mmol). The mixture was stirred at RT for 30 min. 4-Chloro-5-iodopyrimidine (0.30 g, 1.248 mmol) was added and the reaction mixture was heated at 80° C. overnight. The reaction mixture was quenched with water and the solution was extracted with EtOAc (3×). The organic solution was washed with 5% aqueous lithium chloride solution and brine. The organics were dried over MgSO4, filtered, and concentrated. The crude was purified by silica gel column chromatography (10% to 50% EtOAc/hexane) to obtain 2,5-difluoro-4-(5-iodopyrimidin-4-yloxy)benzenamine (160 mg, 36.7% yield) which was used for the next reaction. MS (ESI) m/z: 349.9 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([C:19](=[N:21][O:22]C3CCCCO3)[CH3:20])=[C:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.Cl.[OH-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([C:19](=[N:21][OH:22])[CH3:20])=[C:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(C(C)=NOC1CCCCO1)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(C(C)=NO)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 1-(4-chlorobenzoyl)-5-methoxy-2-methyl -3-[1-[[(tetrahydro-2H-pyran-2-yl)oxy]imino]ethyl]-lH-indole (5.0 g, 11.3 mmol) in tetrahydrofuran (115 ml) is added 10 ml of concentrated hydrochloric acid. The reaction mixture is stirred for 21/2 hours, at which time it is neutralized with concentrated ammonium hydroxide. It is concentrated to near dryness, diluted with ethyl acetate and washed twice with water and once with a saturated solution of sodium chloride. The organic phase is further dried over magnesium sulfate, filtered, and concentrated slowly in vacuo to 50 ml. The powdery crystals are collected to give 2.8 g (70.4%) of pure 1-(4-chlorobenzoyl)-3-[1-(hydroxyimino)ethyl]-5-methoxy-2-methyl-lH-indole; mp darkens (chars) at 170°-197° C. (dec).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19]C(OC(C)(C)C)=O)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.C(OC(=O)NC1C=CC=C(C=O)C=1)(C)(C)C.[C:43]([NH:47]C(C1CCNCC1)=O)([CH3:46])([CH3:45])[CH3:44]>>[C:43]([NH:47][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[CH2:10][CH2:11]1)=[O:5])([CH3:46])([CH3:45])[CH3:44]
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Reactant: CC(C)(C)NC(=O)C1CCNCC1
Agent: CC(C)(C)OC(=O)Nc1cccc(C=O)c1
Product: CC(C)(C)NC(=O)C1CCN(Cc2cccc(N)c2)CC1

Procedure:
The title compound is prepared according to the reaction 1.001a and 1.001d described above using (3-formyl-phenyl)-carbamic acid tert-butyl ester and piperidine-4-carboxylic acid tert-butylamide: LC-MS A: tR=0.44 min; [M+H]+=289.92.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4]([Cl:17])[N:3]=1.[CH3:18][C:19]([CH3:24])([CH2:22][NH2:23])[CH2:20][NH2:21]>[Cl-].[Na+].O>[Cl:17][C:4]1[N:3]=[C:2]([NH:21][CH2:20][C:19]([CH3:24])([CH3:18])[CH2:22][NH2:23])[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: CC(C)(CN)CN
Reactant: Clc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(CN)CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1

Procedure:
A mixture of Example 61a (1.70 g, 6.44 mmol) and 2,2-dimethylpropane-1,3-diamine (10 mL) was heated in a Biotage microwave reactor at 160° C. for 25 minutes. The solution was diluted with 20% brine and washed with EtOAc (2×). The combined organic layers were washed with 20% brine, dried (MgSO4), filtered, and concentrated. The residue was triturated with EtOAc and diethyl ether. The solids were filtered, washed with ether, and dried to give 1.19 g of the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 0.87 (s, 6H), 2.36 (s, 2H), 3.16 (d, J=6.10 Hz, 2H), 6.78-6.89 (m, 2H), 6.97 (d, J=1.02 Hz, 1H), 7.21 (dd, J=7.97, 4.58 Hz, 1H), 8.13 (s, 1H), 8.27-8.38 (m, 2H). MS (ESI+) m/z 329.9 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([N:31]=C=O)(=[O:30])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:23]([NH2:31])=[O:30])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1ccccc1C(=Cc1ccnc(N)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccccc1C(=Cc1ccnc(NC(N)=O)c1)c1ccccc1
Temperature: 50 °C
Yield: 64.1 %

Procedure:
The crude 4-(2-phenyl-2-o-tolyl-vinyl)-pyridin-2-ylamine (251 mg) is dissolved in methylene chloride (5 mL). Then benzoyl isocynate (258 mg, 1.75 mmol) is added. The reaction mixture is sealed and heated at 50° C. for 16 hour. The solvent is then carefully removed and to the residue are added ethanol (5 mL) and potassium carbonate (182 mg, 1.32 mmol). The resulting mixture is heated at 80° C. for 45 min. Then solvent is removed and the residue is partitioned between water (45 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 185 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].Br[C:24]1[S:28][C:27]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:24]4[S:28][C:27]([S:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)(=[O:30])=[O:31])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(S(=O)(=O)N5CCN(C)CC5)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.16) (159 mg, 0.5 mmol) and 1-(5-bromo-thiophene-2-sulfonyl)-4-methyl-piperazine (example B.50) (163 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (200 mg, 71%). MS (ISP) 562.3 [(M+H)+]; mp 191° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.Cl.[NH2:22][C:23]([NH2:25])=[NH:24].[CH3:26][O-].[Na+]>CO>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:26][N:22]=[C:23]([NH2:25])[N:24]=2)=[CH:6][CH:5]=1
Reactant: COC(OC)c1ccc(C(O)Cc2ccccc2)cc1
Reactant: C[O-]
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(-c2nc(N)ncc2-c2ccccc2)cc1

Procedure:
5 g of the product of step 1 and 3 g guanidine hydrochloride are dissolved in 100 ml methanol and 2.7 g of NaOMe is added. The mixture is heated to reflux for 17 h. The product is precipitated upon dilution of the mixture with water and is collected by filtration and washed twice with water.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28](OC)=[O:29])=[CH:25][C:24]=4[CH:32]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][NH2:35]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([NH:35][CH3:34])=[O:29])=[CH:25][C:24]=4[CH:32]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(C(C)(C)C)c4)n3)ccc2o1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(C(C)(C)C)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, N4-(3-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine and methylamine hydrochloride were reacted to give N4-(3-tert-butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofur-5-yl]-2,4-pyrimidinediamine. LCMS: ret. time: 23.05 min.; purity: 100%; MS (m/e): 434 (MH+); 1□□□ (DMSO-d6): δ 9.6 (1H, s), 9.57 (1H, s), 8.75 (1H, m), 8.25 (1H, s), 8.15 (1H, s), 7.93 (1H, d, J=8.5 Hz), 7.47 (3H, m), 7.44 (1H, s), 7.36 (1H, t, J=8.5 Hz), 7.25 (1H, d, J=8.5 Hz), 2.89 (3H, d, J=4.5 Hz), 1.33 (9H, s).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>CC(C)=O.O=[Mn]=O>[N:1]1([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1cnn(CCCN2CCc3ccccc32)c1
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: Nc1cnn(CCCn2ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-[3-(2,3-dihydro-indol-1-yl)-propyl]-1H-pyrazol-4-ylamine (200 mg, 0.83 mmol) in acetone (1.0 mL) was added dropwise to a suspension of MnO2 (275 mg, 3.17 mmol) in acetone (2.0 mL). The resulting dark reaction mixture was stirred at rt overnight, then filtered over celite, washed with acetone and the solvent was removed under reduced pressure to yield the title compound which was used without further purification in the next step. LC-MS conditions B: tR=0.51 min, [M+H]+=241.20.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])[NH:11][C:10]=1[C:24]([OH:26])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:27]([O:34][CH2:35][CH2:36][NH:37][CH:38]([CH3:40])[CH3:39])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Si:27]([O:34][CH2:35][CH2:36][N:37]([CH:38]([CH3:40])[CH3:39])[C:24]([C:10]1[NH:11][C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])=[N:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:26])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Yield: 51 %

Procedure:
5-(Benzyloxy)-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (68) (1 g, 2.41 mmol, Eq: 1.00) was dissolved in pyridine (20 ml) and N-(2-(tert-butyldimethylsilyloxy)ethyl)propan-2-amine (8b) (576 mg, 2.65 mmol, Eq: 1.1) was added. Precipitate formed and gave a thick slurry. Additional 5 ml of pyridine were added to ease stirring. The suspension was cooled in an ice/NaCl bath. POCl3 (1.11 g, 673 μl, 7.22 mmol, Eq: 3) was added dropwise, keeping the inside temperature below 0° C. After the addition was complete the mixture was stirred for 45 minutes at 0° C. The reaction was quenched with ice and the organic solvent was mostly removed. The remaining aqueous layer was extracted three times with ethyl acetate. The organic layers were washed with brine, combined, dried over Na2SO4, filtered and concentrated. The remaining oil was taken up in a little dichloromethane, was filtered through Celite and then purified by SiO2 flash chromatography (80 g SiO2, hexanes/ethyl acetate 0-50% ethyl acetate) to afford 5-benzyloxy-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (69) (0.758 g, 1.23 mmol, 51.2% yield) as a light brown oil.