Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:12][CH:11]=[CH2:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C=CCBr
Reactant: Cc1cc(C)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C)cc(C)c1

Procedure:
1000 g of 3,5-dimethylphenol (A) were dissolved in 1000 ml of acetone, 980 g of allyl bromide were added dropwise, and 114.8 g of potassium carbonate were subsequently added. The mixture was refluxed for 18 hours and then cooled. The potassium carbonate was filtered off, and the filtrate was treated with 3 000 ml of water. It was extracted three times using tert-butyl methyl ether, and the organic phases were combined and washed twice using in each case 300 ml of 10% strength sodium hydroxide solution. The organic phase was dried over potassium carbonate and filtered, and the filtrate was concentrated. After distillation, 837 g (64% of theory) of allyl 3,5-dimethylphenyl ether of a boiling point of 98 to 110° C. at 10 mbar were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:3]=1[CH:4]=O.[NH2:16][C:17](N)=[O:18]>O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[C:3]2[C:2]=1[N:1]=[C:17]([OH:18])[N:16]=[CH:4]2
Reactant: COc1ccc(C(F)(F)F)c(C=O)c1N
Reactant: NC(N)=O
Solvent: O
Product: COc1ccc(C(F)(F)F)c2cnc(O)nc12
Temperature: 175 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 2-amino-3-methoxy-6-(trifluoromethyl)benzaldehyde (1 eq) (obtained from step 7) and urea (15 equiv.) was heated to 175° C. with vigorous stirring for 2 h. The reaction was cooled to room temperature and water was added. The solid was collected by filtration. Air-dried to give 8-methoxy-5-(trifluoromethyl) quinazolin-2-ol as yellow solid in 70% yield. ES/MS m/z 245.0 (MH+).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](Cl)[C:12]=2[N+:18]([O-:20])=[O:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:1]1([S:7]([CH2:10][C:11]2[C:12]([N+:18]([O-:20])=[O:19])=[C:13]([N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1c(Cl)cccc1CS(=O)(=O)c1ccccc1
Product: CN1CCN(c2cccc(CS(=O)(=O)c3ccccc3)c2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
10 g of 1-benzenesulfonylmethyl-3-chloro-2-nitro-benzene were slurried in 25 mL N-methylpiperazine under nitrogen and stirred. The mixture was heated to 80° C. (oil bath temperature) for a period of 14 hours. The reaction was quenched at 80° C. with 125 mL water, and the thick slurry was filtered, washed with 100 mL water and 100 mL hexanes., and vacuum dried at 45° C. under nitrogen purge for 4 hours, to yield 11.7 g of 1-(3-benzenesulfonylmethyl-2-nitro-phenyl)-4-methyl-piperazine mp 180-182° C.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4]1.[F:11][C:12]([F:21])([F:20])[CH2:13][CH2:14][CH:15]([C:18]#[N:19])[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][N:3]([CH2:2][C:15]([CH2:14][CH2:13][C:12]([F:11])([F:20])[F:21])([C:16]#[N:17])[C:18]#[N:19])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccn(CCl)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
0.61 g of 1-chloromethyl-3-nitro-1H-pyrole and 0.65 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 10 ml of N,N-dimethylformamide. 0.28 g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.80 g of [(3-nitro-1H-pyrole-1-yl) methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (45), hereinafter) shown by below formula.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:27])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16](OCC[Si](C)(C)C)[C:17](C)=[CH:18][C:11]=23)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29].CO.[NH4+].[OH-]>>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[C:1]([C:5]1[N:6]([CH3:27])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][CH:17]=[CH:18][C:11]=23)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2c(-c3cn(C)c(C(C)(C)C)n3)ccnc2n1OCC[Si](C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cn1cc(-c2ccnc3[nH]ccc23)nc1C(C)(C)C
Yield: 94 %

Procedure:
A solution of 4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)-1-[2-(trimethylsilyl)-ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine (0.010 g, 0.000026 mol) in TFA (3 mL, 0.04 mol) was stirred for 2 hours. Then the excess TFA was evaporated and the residue was stirred in methanol (3 mL, 0.07 mol) and NH4OH (1 mL) for 16 hours. The solvents were removed and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)-1H-pyrrolo[2,3-b]pyridine, trifluoroacetate salt (9 mg, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19](=[O:48])[N:20]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:21]=[C:22]([NH:24][C:25]([C:27]2[CH:28]=[N:29][N:30]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[CH:31]=2)=[O:26])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:51][CH2:52][N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19](=[O:48])[N:20]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[CH:21]=[C:22]([NH:24][C:25]([C:27]2[CH:28]=[N:29][N:30]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[CH:31]=2)=[O:26])[CH:23]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: ClCCN1CCCCC1
Reactant: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(O)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(OCCN6CCCCC6)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Temperature: 50 °C

Procedure:
To a solution of intermediate (11e), 5-hydroxy-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]indole-1-carboxylic acid tert-butyl ester (150 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL) was added 1-(2-chloroethyl)-piperidine hydrochloride (62 mg, 0.33 mmol) and cesium carbonate (219 mg, 0.67 mmol). The reaction mixture was heated at 50° C. for 5 hours, and cooled to ambient temperature. The reaction mixture was cooled and partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. The title compound was purified by flash chromatography on SiO2 eluting with dichloromethane—5% methanol/dichloromethane (gradient) to afford the desired title compound as a pale yellow solid, 94 mg, 54%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24](=[N:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=1)[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH2:34][CH2:35][OH:36])[C:26]=1[F:37]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[N:10]1[C:21](=[O:20])[NH:22][C:23]([CH:24]([NH:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]#[N:46])=[CH:43][CH:44]=2)[C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH2:34][CH2:35][OH:36])[C:26]=2[F:37])=[N:11]1)=[O:4]
Reactant: COC(=O)c1scnc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCO)c1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1scnc1-n1nc(C(Nc2ccc(C#N)cc2)c2cc(OC)cc(OCCO)c2F)[nH]c1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
After adding 153 mg of 4-hydrazinothiazole-5-carboxylic acid methyl ester (Example (162c)) and 600 μl of triethylamine to a solution of 394 mg of {2-(4-cyanophenylimino)-2-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-1-methylsulfanylethylidene}carbamic acid methyl ester in 6 ml of THF, the mixture was stirred at 60° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was concentrated, the residue was dissolved in 5 ml of DMF, 600 μl of triethylamine was added and the mixture was stirred overnight at 85° C.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[O:13]=[C:14]1[NH:18][C:17](=[O:19])[O:16][N:15]1[CH2:20][C:21]1[CH:43]=[CH:42][C:24]([O:25][CH2:26][C:27]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([OH:41])=O)=[CH:35][CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1.[CH2:44]([O:46][CH2:47][CH2:48][NH2:49])[CH3:45].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[O:13]=[C:14]1[NH:18][C:17](=[O:19])[O:16][N:15]1[CH2:20][C:21]1[CH:43]=[CH:42][C:24]([O:25][CH2:26][C:27]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([NH:49][CH2:48][CH2:47][O:46][CH2:44][CH3:45])=[O:41])=[CH:35][CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccc(-c2cccc(COc3ccc(Cn4oc(=O)[nH]c4=O)cc3)c2)cc1
Reactant: CCOCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1ccc(-c2cccc(COc3ccc(Cn4oc(=O)[nH]c4=O)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
WSC hydrochloride (163 mg) was added to a mixture of 3′-({4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-4-biphenylcarboxylic acid (293 mg), (2-ethoxyethyl)amine (0.11 ml), HOBt (142 mg) and DMF (10 ml), followed by stirring at room temperature for 27 hours. The solvent was evaporated under a reduced pressure, and chloroform/methanol (4/1) was added to the residue, followed by washing with water and a saturated ammonium chloride aqueous solution. The solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol), the resulting foamy substance was further crystallized by adding diethyl ether, and the resulting crystals were recrystallized from methanol to obtain 3′-({4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-N-(2-ethoxyethyl)-4-biphenylcarboxamide (135 mg) as white crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:27]([C:29]1[NH:30][CH:31]=[CH:32][N:33]=1)[CH3:28]>>[CH:15]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:18]([C:20]2[CH:25]=[N:24][C:23]([N:30]3[CH:31]=[CH:32][N:33]=[C:29]3[CH2:27][CH3:28])=[N:22][CH:21]=2)=[O:19])[CH2:17][CH2:16]1
Reactant: CCc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Product: CCc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1

Procedure:
The title compound is prepared from 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester and 2-ethyl-1H-imidazole following procedures analogous to those described in Intermediate 16 and Intermediate 17. LC (method 10): tR=0.56 min; Mass spectrum (ESI+): m/z=341 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:16]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])([CH3:18])[CH3:17]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:22][CH2:21][CH2:20][O:19][CH:16]([CH3:18])[CH3:17])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)OCCCN
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Reaction time: 48 h

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (40 g) was dissolved in dichloromethane (1.4 L) and triethylamine (23.3 mL). 3-Isopropoxypropylamine (19.3 mL) was added dropwise. After 48 hours, the reaction mixture washed successively with water and saturated aqueous sodium chloride. The organic fraction was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. (7-Bromo-3-nitroquinolin-4-yl)-(3-isopropoxypropyl)amine was isolated as a tan solid (51.2 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH2:30])[O:26][C:25]3=[O:31])=[CH:20][C:19]=2[F:32])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(O)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:33](=[O:35])[CH3:34])[O:26][C:25]3=[O:31])=[CH:20][C:19]=2[F:32])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CN(c2ccc(NC3CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1
Solvent: CC(=O)O
Product: CC(=O)NC[C@H]1CN(c2ccc(NC3CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1

Procedure:
A solution of 450 mg 4-[4-{(5S)-5-aminomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenylamino]-piperidine-1-carboxylic acid benzyl ester (1.01 mmol), 2 ml acetic acid and 0.093 ml (1 mmol) acetic anhydride was stirred at RT for 1 h. The solvents were evaporated.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[C:20]([CH:22]1[NH:27][CH2:26][CH2:25][NH:24][CH2:23]1)#[CH:21]>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:24]4[CH2:25][CH2:26][NH:27][CH:22]([C:20]#[CH:21])[CH2:23]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: C#CC1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: C#CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Temperature: 140 °C
Yield: 13.5 %

Procedure:
A mixture of 1.23 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.95 g of 3-ethynylpiperazine and 15 ml of pyridine is heated at 140° C. in a pressure bottle for 18 hours and then purified as described in Example 101, giving 210 mg of the desired product.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][N:13]([CH:16]=[CH2:17])[C:12]1=[O:18])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][N:13]([CH:16]=[CH2:17])[C:12]1=[O:18]
Reactant: C=CN1CCC(CCO[Si](C)(C)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CN1CCC(CCO)C1=O
Temperature: 25 °C

Procedure:
To a stirred and ice-cold solution of 3-[2-(tert-butyldimethylsilanyloxy)-ethyl]-1-vinylpyrrolidin-2-one (TBSE-VP) (269 mg; 1.0 mmol) in dry tetrahydrofuran (10 mL) was dropwise added a 1.0 M solution of tetrabutylammonium fluoride (2.0 mL; 2.0 mmol; 2.0 equiv.) under an argon atmosphere. Upon completion of the addition the reaction mixture was left stirring at 0° C. for 5 min, allowed to warm to ambient temperature over 5 min and left stirring for another 40 min. The reaction mixture was partitioned between water (5 mL) and ethyl acetate (10 mL) and the aqueous phase was extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Column chromatography (ethyl acetate) afforded the target compound (135 mg; 0.87 mmol; 87%) as a pale yellow liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8]C(=O)C)=[C:4](F)[CH:3]=1.O.[NH2:14][NH2:15].C([O-])(O)=O.[Na+]>C(O)C>[NH:14]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH:8]=[N:15]1
Reactant: CC(=O)Cc1ccc(Br)cc1F
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2[nH]ncc2c1
Temperature: 162.5 °C
Yield: 148.8 %

Procedure:
A solution of 4-bromo-2-fluoro-N-methoxy-N-methyl-benzamide (CAS [801303-33-3]) (24.9 g, 95.0 mmol) in THF (100 mL) at −78° C. was treated with a 3 N solution of ethyl magnesium bromide in diethyl ether (33.25 mL, 115 mmol) and allowed to warm to 0 C and stir for a 6 h period, after which time the reaction mixture was quenched with a half saturated aqueous solution of NH4Cl (200 mL) and EtOAc (100 mL). The mixture was separated and the organic component, washed with brine (2×50 mL), dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 20% EtOAc/hexanes as eluant to afford 1-(4-bromo-2-fluorophenyl)-propanone as a pale yellow solid (16.25 g, 74%). The propanone (21.15 g, 91.6 mmol) was then dissolved in ethanol (100 mL), treated with hydrazine hydrate (4.9 mL, 100.7 mmol), and heated at reflux for 4 h. The reaction mixture was then evaporated and dissolved in ethylene glycol (100 mL) and heated at 160-165° C. for 8 h after which time the cooled reaction mixture was poured onto water (500 mL) with stirring. The aqueous mixture was neutralized, with rapid stirring, using a small amount of an aqueous saturated solution of NaHCO3 to afford a pale yellow precipitate. The solids were filtered, washed with water, and air dried to afford cyclized indazole product (16.1 g, 78%).
Reaction SMILES: [S:1]([CH2:4][C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[N:10]1C(=O)C2=CC=CC=C2C1=O)[C:2]#[N:3].O.NN.[ClH:24]>O1CCOCC1>[ClH:24].[S:1]([CH2:4][C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH2:10])[C:2]#[N:3]
Reactant: N#CSC[C@H]1NC(=O)[C@H]1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: C1COCCO1
Solvent: O
Product: N#CSC[C@H]1NC(=O)[C@H]1N
Temperature: 20 °C
Reaction time: 0.83 h

Procedure:
A hot mixture of 1.45 g of the product of Step B in 15 ml of hot dioxane was cooled and 0.3 ml of hydrazine hydrate was added thereto. The mixture was stirred for 50 minutes at 20° C. and 7.5 ml of N hydrochloric acid were added thereto. The mixture was stirred for 15 hours and vacuum filtered. The filtrate was rinsed with water and the filtrate was evaporated to dryness to obtain 0.914 g of cis 4-thiocyanatomethyl-3-amino-2-oxo-azetidine hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[NH4+]>[NH2:22][C:21]1[CH:20]=[CH:19][C:11]([C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccc(C(=O)CCC(=O)O)cc1OCc1ccccc1

Procedure:
A solution of 3-(3-benzyloxy-4-nitrobenzoyl)propionic acid in 5N ammonium hydroxide was added to a well stirred boiling aqueous solution of ferrous sulphate. The pH was adjusted to 9 with concentrated ammonium hydroxide and the mixture was refluxed for 15 minutes. The filtrate was concentrated under reduced pressure and then neutralised with glacial acetic acid to give 3-(4-amino-3-benzyloxybenzoyl)propionic acid.
Reaction SMILES: Br[CH:2]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:6](=[O:14])[C:7]2[CH:13]=[CH:12][CH:11]=[N:10][C:8]=2[N:9]=1)[CH3:3].[CH3:22][NH2:23]>C(O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:5]2[C:6](=[O:14])[C:7]3[CH:13]=[CH:12][CH:11]=[N:10][C:8]=3[N:9]=[C:4]2[CH:2]([NH:23][CH3:22])[CH3:3])=[CH:16][CH:17]=1
Reactant: CN
Reactant: CC(Br)c1nc2ncccc2c(=O)n1-c1ccc(F)cc1
Solvent: CCO
Product: CNC(C)c1nc2ncccc2c(=O)n1-c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A suspension of the bromide (18) (80 mg, 0.23 mmol) and 8.03M solution of methylamine in ethanol (0.64 mL) was heated to 40° C. for 3 h, and stirred at ambient temperature overnight. The resulting suspension was concentrated to dryness under reduced pressure, and the resulting light brown solid was taken up in dichloromethane and filtered through a silica-gel plug to give the title amine (19) (57 mg, 83%) as a beige solid (The crude material was directly taken through the next step without further purification).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:21])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH:14]=[O:15])[C:5]2=[CH:4][N:3]=1.[BH4-].[Na+]>CO.C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:21])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:14][OH:15])[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[C:5]2=[CH:4][N:3]=1
Reactant: COc1ccc(C=O)cc1-c1nn(C)c2nc(N)ncc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1-c1nn(C)c2nc(N)ncc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-benzaldehyde (Example 75) (0.040 g, 0.141 mmol) is suspended in dry MeOH (2.5 ml) and THF (1 ml). The reaction mixture is cooled to 0-5° C. (ice-bath) and sodium borohydride (0.006 g, 0.1551 mmol) is cautiously added. The reaction mixture is stirred at room temperature for 24 hours, filtered, washing with MeOH and concentrated in vacuo. The resulting solid is triturated in MeOH (minimal) and collected by filtration to afford the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[NH:16])SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:17][CH2:18][CH2:19][CH2:20]N>CC(O)C>[NH:17]1[CH2:18][CH2:19][CH2:20][NH:16][C:13]1=[N:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:11]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCN
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)N=C2NCCCN2)nc1Cl
Temperature: 60 °C

Procedure:
1-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (1.0 g, 2.58 mmol) is suspended in propan-2-ol (10 ml) and 1,3-diaminopropane (0.32 ml, 3.9 mmol) is added. The mixture is heated at 60° C. for 18 hours and then allowed to cool to room temperature and the solids present are collected by filtration. The solids are washed with THF and MeOH to yield the title compound as a yellow solid; [M+H]+ 270
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:22]([NH2:24])[CH3:23]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:24][CH2:22][CH3:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CCNCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Ethylamine were converted to yield {3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-ethyl-amine as white solid, MS: 391 (MH+,1Br).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Br)([CH3:12])[CH3:11]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)[Mg]Br
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a flame-dried flask under an argon atmosphere is added 1.85 g of commercially available 4-bromobenzaldehyde and charged with 30 mL of tetrahydrofuran. The solution is cooled to 0 ° C. and slowly treated with 7.0 mL of isopropylmagnesium bromide. After stirring overnight at room temperature the reaction mixture is concentrated under reduced pressure. The residue is partioned between diethyl ether and saturated ammonium chloride; the aqueous layer is then extracted with diethyl ether. The combined organic phases are dried (magnesium sulfate), and the volatiles are removed. The residue is flash column chromatographed using 30% to 60% diethyl ether in hexane to afford 1.25 g of the title product as a viscous, tan oil.