Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([CH:13]1[NH:12][C:10](=[O:11])[N:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:21]1=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C=Nc1cc(F)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NC(Cc2ccccc2)C(=O)N1c1cc(F)ccc1F
Reaction time: 8 h
Yield: 82.8 %

Procedure:
2,5-Difluorophenylisocyanate (1.55 g, 10.0 mmol) in methylene chloride (25 mL) was added dropwise to a suspension of phenylalanine (1.65 g, 10.0 mmo) in methylene chloride (50 mL) containing triethylamine (1.4 mL, 1.01 g, 10.0 mmol). The solution was allowed to stir overnight, and was then concentrated. The residue was taken up into 6N HCl and heated to reflux for 3 hours. The cooled solution was extracted with ethyl acetate (3×), and the combined extracts where washed with water (2×), dried (over MgSO4), filtered and concentrated to give 2.7 grams. Purification by column chromatography gave 2.5 grams of 5-benzyl-3-(2,5-difluorophenyl)imidazolidine-2,4-dione.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[F:5][C:6]([F:13])([F:12])[C:7](=[CH2:11])[C:8](O)=[O:9]>C(OC(=O)C)(=O)C>[F:5][C:6]([F:13])([F:12])[CH:7]1[CH2:11][NH:4][C:2](=[O:3])[NH:1][C:8]1=[O:9]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: NC(N)=O
Solvent: CC(=O)OC(C)=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1
Yield: 66.4 %

Procedure:
In 160 ml of acetic anhydride, 13.5 g of urea was suspended and 30 g of trifluoromethacrylic acid was added to the suspension. The resulting mixture was allowed to react at 100° C. for 1 hour and the reaction mixture was concentrated under reduced pressure. The obtained oil was crystallized from 150 ml of water and then recrystallized from 150 ml of water to obtain 25.9 g of 5-trifluoromethyl-5,6-dihydrouracil.
Reaction SMILES: FC(F)(F)C1C=CC(OCC2C=CC(SC3C=CC(OCC(O)=O)=C(C)C=3)=CC=2)=CC=1.C([O:34][C:35](=[O:68])[CH2:36][O:37][C:38]1[C:47]2[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=2[C:41]([S:48][C:49]2[CH:54]=[CH:53][C:52]([CH2:55][NH:56][C:57]3[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=3)=[CH:51][C:50]=2[Cl:67])=[CH:40][CH:39]=1)C>>[Cl:67][C:50]1[CH:51]=[C:52]([CH2:55][NH:56][C:57]2[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:64])[F:65])=[CH:59][CH:58]=2)[CH:53]=[CH:54][C:49]=1[S:48][C:41]1[C:42]2[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=2[C:38]([O:37][CH2:36][C:35]([OH:68])=[O:34])=[CH:39][CH:40]=1
Reactant: CCOC(=O)COc1ccc(Sc2ccc(CNc3ccc(C(F)(F)F)cc3)cc2Cl)c2c1CCCC2
Agent: Cc1cc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O
Product: O=C(O)COc1ccc(Sc2ccc(CNc3ccc(C(F)(F)F)cc3)cc2Cl)c2c1CCCC2

Procedure:
The title compound was prepared according to the method described for preparing compound 7, using compound 22.5 as the starting material. MS APSI m/e: 520 (M−H). 1H NMR (400 MHz) (DMSO-d6) δ 13.03 (1H, brs); 7.43 (1H, s); 7.35 (2H, d, J=8.6 Hz); 7.31 (1H, d, J=8.5 Hz); 7.16 (1H, d, J=8.2 Hz); 6.98 (1H, t, J=6.0 Hz); 6.78 (1H, d, J=8.6 Hz); 6.64 (2H, d, J=8.6 Hz); 6.48 (1H, d, J=8.2 Hz); 4.75 (2H, s); 4.26 (2H, d, J=5.9 Hz); 2.66-2.63 (4H, m); 1.66-1.65 (4H, m).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:36][C:37]([CH3:41])=[C:38]([NH2:40])[CH:39]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:36][C:37]([CH3:41])=[C:38]([NH:40][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:39]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: Cc1sc(S(=O)(=O)NC(C)(C)CO)cc1N
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1sc(S(=O)(=O)NC(C)(C)CO)cc1NC(=O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-methyl-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.12) according to general procedure II. Yellow solid. MS (ISP) 602.2 [(M−H)−]; mp 180° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCCCCCCCl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1ccc(-c2ccc(OCCCCCCCCO)cc2)cc1
Yield: 59.2 %

Procedure:
A solution of 5.0 g of 4'-hydroxybiphenyl-4-carbonitrile and 5.1 g of 8-chloro-1-octanol in 100 ml of ethyl methyl ketone was treated with 14.1 g of finely powdered potassium carbonate and the mixture was heated under slight reflux overnight. The suspension was suction filtered and the filtrate was concentrated in a vacuum. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) gave 4.9 g of 4'-(8-hydroxyoctyloxy)biphenyl-4-carbonitrile.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH3:15])[N:13]=[C:12]([NH:16][C:17](=[O:25])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:6][CH:5]=1.[CH3:32]I>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH3:15])[N:13]=[C:12]([N:16]([CH3:32])[C:17](=[O:25])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[CH:6][CH:5]=1
Reactant: Cn1nc(NC(=O)Cc2ccccc2)c(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)Cc1ccccc1)c1nn(C)c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
While 2 1m of a dimethylformamide suspension containing 20 mg of 60% sodium hydride was being cooled with ice, 3 ml of a dimethylformamide solution containing 180 mg of 5-(4-fluorophenyl)-1-methyl-3-phenylacetylamino-4-(4-pyridyl)pyrazole was added dropwise thereto, followed by stirring at room temperature for 30 minutes. Then, 2 ml of a dimethylformamide solution containing 80 mg of methyl iodide was added dropwise thereto, followed by stirring at room temperature for 2 hours. After the dimethylformamide was distilled off under reduced pressure, the resulting residue was purified by column chromatography using 30 g of silica gel [with an elution solvent comprising chloroform-methanol (70:1)]. Thus, 149.2 mg (80% yield) of the title compound was obtained as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Br[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([OH:30])=[O:29])[CH:23]=1.C(O)=O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]([OH:30])=[O:29])[CH:23]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C(O)c1cc(Br)ccn1
Solvent: O=CO
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3ccnc(C(=O)O)c3)CC1)C(=O)N2

Procedure:
7.0 g (25 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 2.5 g (12 mmol) 4-bromopicolinic acid in 25 mL NMP were stirred for 2 h at 110° C. The reaction mixture was combined with some formic acid and purified by preparative HPLC-MS. The product-containing fractions were combined and evaporated down. The residue was stirred with MeOH, suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6](=[O:23])[C:5]2([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])[NH:24][C:25]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:26].[H][H]>CCO.C1COCC1.[Ni]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[C:5]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])([NH:24][C:25]([N:27]([CH2:28][CH3:29])[CH2:30][CH3:31])=[O:26])[C:6]2=[O:23])(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CCN(CC)C(=O)NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc21
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(CC)C(=O)NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(N)cc2)c2ccc(Cl)cc21

Procedure:
7.6 g of the compound obtained in EXAMPLE 12 in 100 ml of EtOH and 50 ml of THF are reduced with hydrogen under a pressure of 50 bar for 6 hours at RT, in the presence of 2 g of Raney nickel. The mixture is filtered on C elite and the filtrate is evaporated under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=3.2 g. M.p.=210° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH3:23])=[C:9]([NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[CH:10]=1)[NH2:4].[Cl:24][CH2:25][C:26](OC(=O)CCl)=O>CN1C(=O)CCC1.O>[Cl:24][CH2:25][C:26]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[CH:7][C:8]([CH3:23])=[C:9]([NH:11][C:12]([C:14]3[N:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]4=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:4]=1
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(-c2noc(CCl)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 110 °C

Procedure:
A mixture of N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (500 mg, 1.62 mmol) and 2-chloroacetic anhydride (553 mg, 3.23 mmol) in anhydrous NMP (10 mL) was heated in the microwave at 110° C. for 12 minutes. The crude was diluted with water and extracted with ethyl acetate. The organic was washed with a water/brine mixture and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified by silica chromatography to yield N-(5-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (38). MS m/z 378.9 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O.N1C=CC=CC=1.ClC(OC)=O>C(Cl)Cl>[CH3:1][O:5][C:6](=[O:33])[N:7]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])[CH3:8]
Reactant: CN(CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Agent: COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N(C)CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{2-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-ethyl}-methyl-carbamic acid tert-butyl ester (25 mg, 0.055 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 1 h. Solvent and excess TFA were removed in vacuo. To the residue were added CH2Cl2 (2 mL), pyridine (0.072 mL, 0.88 mmol), and methyl chloroformate (0.034 mL, 0.44 mmol), and the resulting mixture was stirred for 16 h. The mixture was diluted with CH2Cl2 and washed with 1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was dissolved in 5 mL of 0.5 M NaOMe solution and refluxed for 1 h. After cooling to r.t., the mixture was acidified to pH about 2 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (0-5% MeOH/CH2Cl2) to give the desired product and an impurity. The crude product was then treated with a mixture of 1 M NaOH and MeOH (1:1 v/v) for 16 h at r.t. The mixture was acidified to pH about 2 and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated, and the crude product was purified by chromatography (0-5% MeOH/CH2Cl2) to give 6.3 mg of the title compound. MS: (+) m/z 411.25 (M+1).
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3].I[CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]=[CH:16]1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH3:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])([CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]=[CH:16]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Reactant: ICCn1cnc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(CCn1cnc(-c2ccccc2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of Ethyl 2-(methylsulfonyl)propanoate (377 mg, 2.09 mmol, 1 eq) and 1-(2-iodoethyl)-4-phenyl-1H-imidazole (623 mg, 2.09 mmol, 1 eq) in DMF (7 mL) was added Cs2CO3(1.70 g, 5.22 mmol, 2.5 eq) and the reaction mixture was allowed to stir overnight at RT, then for a further 24 h at 45° C. EtOAc was added and the mixture was washed with water. The organic layer was dried over MgSO4, filtered and concentrated. The crude product mixture was purified by flash chromatography on silica gel eluting with 10-95% ethyl acetate in heptanes to give ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-imidazol-1-yl)butanoate (335 mg, 46% yield). LC-MS M+H+351.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@H:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](=O)[CH3:23].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:27]>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:26](=[O:27])[N:21]([C@H:10]2[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=3)[CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[CH2:22][CH3:23])=[CH:30][CH:31]=1
Reactant: N[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1
Reactant: CC=O
Reactant: O=C(Cl)Oc1ccc(F)cc1
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1

Procedure:
In analogy to the procedure described for the synthesis of rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester (example 1, step g & h) the title compound was prepared from (3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-ylamine through reductive amination with acetaldehyde followed by reaction with 4-fluorophenyl chloroformate to yield the title compound as light brown oil. MS m/e: 471.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.CC(N)C(C)[NH2:14].[CH2:17]([N:19]([CH2:22]C)[CH2:20]C)[CH3:18].C(#N)C>O>[CH3:20][N:19]([CH3:22])[CH2:17][CH2:18][NH:14][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCN(CC)CC
Reactant: CC(N)C(C)N
Solvent: O
Solvent: CC#N
Product: CN(C)CCNc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 9 h
Yield: 41.5 %

Procedure:
To a round bottom flask, charged with 2-chloro-5-nitropyridine (1.0 g, 6.3 mmol), dimethylethane-1,2-diamine (0.55 g, 6.3 mmol), triethylamine (0.63 g, 6.3 mmol) and acetonitrile (10 mL). The resulting reaction mixture was stirred at ambient temperature for 9 hours. TLC analysis showed no acid remaining so the mixture was diluted with water and extracted with ethylacetate. The organic layer was separated and washed with brine and water, dried (Na2SO4) and concentrated. The crude material was purified by silica gel chromatography using a 95:5 mixture of dichloromethane and methanol as eluent to afford the title product as a brown solid (0.55 g, 42% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.91 (1H, m), 8.09 (2H, m), 6.62 (1H, m), 4.10 (1H, m), 3.50 (2H, m), 3.17 (2H, m), 2.21 (6H, s). MS m/z: 211.14 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C=CC=CC=1)(=O)C.C(=O)C1C=CC=CC=1.[H][H]>[Ni].[Mo].C1(C)C=CC=CC=1>[CH:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][OH:9])=[CH:2][CH:3]=1
Reactant: O=CCc1ccccc1
Reactant: [H][H]
Agent: [Mo]
Agent: [Ni]
Solvent: CC(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=Cc1ccccc1
Product: OCCc1ccccc1

Procedure:
The toluene layers (about 4.7 l) were collected and the toluene was evaporated under reduced pressure. The residual liquid was fed to a fractionating column under reduced pressure. Thus, the remaining toluene was at first evaporated, then styrene (35 g) was recovered at 35° C./10 mmHg and fractional distillation was further conducted at 100° to 110° C. (bath temperature) to obtain a distillate (73 g) boiling at 45° to 50° C./2 mmHg. This distillate was found to be a mixture of phenylacetaldehyde (78 wt.%), acetophenone (19 wt.%) and benzaldehyde (3 wt.%) according to gas chromatographic analysis. The thus obtained mixture, 100 ml of toluene and 5 g of Raney nickel catalyst modified with molybdenum (Mo/Ni=6/94 atomic ratio) were fed into an autoclave of 500 ml capacity equipped with a magnetic stirrer, and hydrogenation was carried out at room temperature under 500 atm. of hydrogen pressure for 20 hours. After the reaction, the catalyst was filtered off from the reaction mixture. The filtrate was evaporated to remove the toluene by a rotary evaporator. The remaining liquid was subjected to fractional distillation under reduced pressure of 10 mmHg, whereby benzyl alcohol (1.8 g) boiling at 75° C./10 mmHg, α-phenethyl alcohol (13.1 g) boiling at 87° C./10 mmHg and β-phenethyl alcohol (53.8 g) boiling at 97° C./10 mmHg were obtained. Thus-obtained β-phenethyl alcohol had a refraction index nD20 =1.533 and no halogen according to halogen-detective test and showed no other peaks on the gas chromatogram.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Si](C=[N+]=[N-])(C)(C)[CH3:15].CC(O)=O>CO.C(#N)C>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 74.3 %

Procedure:
To 3-chloro-2-nitrobenzoic acid (3.15 g, 15.6 mmol) in methanol/acetonitrile (20 mL/20 mL) was dropwise added TMSCHN2 (2N in hexanes, 11.7 mL, and 23.4 mmol) at 0° C. under N2 over 10 min until the yellow color persist. The mixture was continued stirring for 20 min, followed by dropwise addition of HOAc until the yellow color disappeared to kill excessive TMSCHN2. Partial of the solvent was removed on rotary vacuum, the product came out solution as a light yellow solid, which was filtered and washed with Et2O (2×2 mL) to afford the expected product as a white solid (2.5 g, 74% yield); 1H NMR (400 MHz, CDCl3) δ ppm 3.91 (s, 3 H), 7.51 (t, J=8.06 Hz, 1 H), 7.70 (dd, J=8.06, 1.26 Hz, 1 H), 7.97 (dd, J=7.81, 1.26 Hz, 1 H); Mass spec. 216.02 (MH+), Calc. for C8H6ClNO4 215.00.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:9]([O:10][CH2:11][CH:12]([OH:19])[CH2:13][NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].Cl[C:21](OC)=[O:22].C[O-].[Na+]>C(O)(C)C.O.CO>[C:15]([NH:14][CH2:13][CH:12]([OH:19])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH2:2][NH:1][C:21](=[O:22])[NH:5]2)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)NCC(O)COc1cccc(N)c1CN
Reactant: COC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: CC(C)(C)NCC(O)COc1cccc2c1CNC(=O)N2

Procedure:
Analogously to Example 4(f), 8.0 g of 2-aminomethyl-3-(3-tert.-butylamino-2-hydroxy-propoxy)-aniline are reacted first with 3.3 g of methyl chloroformate in a mixture of 28 ml of isopropanol and 28 ml of water and then with 3.2 g of sodium methylate in 30 ml of methanol. After working up, 5-(3-tert.-butylamino-2-hydroxy-propoxy)-3,4-dihydro-1H-quinazolin-2-one with a melting point of 204°-205° is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]2[C:4]=1[C:5](=[O:22])[C:6]1[CH:7]=[CH:8][C:9]([C:20]#[N:21])=[CH:10][C:11]=1[C:12]2=[O:19].[N-:23]=[N+:24]=[N-:25].[Na+].Cl.C(N(CC)CC)C.Cl>O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]2[C:4]=1[C:5](=[O:22])[C:6]1[CH:7]=[CH:8][C:9]([C:20]3[NH:25][N:24]=[N:23][N:21]=3)=[CH:10][C:11]=1[C:12]2=[O:19]
Reactant: COc1ccc(OC)c2c1C(=O)c1ccc(C#N)cc1C2=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(OC)c2c1C(=O)c1ccc(-c3nnn[nH]3)cc1C2=O
Temperature: 97 °C
Reaction time: 9 h

Procedure:
9,10-Dihydro-5,8-dimethoxy-9,10-dioxoanthracene-2-carbonitrile (1.005 g), sodium azide (0.334 g), triethylamine hydrochloride (0.708 g), dimethyl formamide (24 ml) and water (0.5 ml) were heated with stirring to 97° C. for 9 hours then cooled and poured into a mixture of water (210 ml) and 5N HCl (30 ml). The precipitate formed was isolated by filtration, washed with water and then dried in vacuo at 70° C. to give the tetrazole as a solid, m.p. 260°-262° C.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[NH2:26][C:27]1[CH:31]=[C:30]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)[NH:29][N:28]=1.NC1C=CNN=1>O1CCCC1>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]2=[CH:2][NH:26][C:27]1[CH:31]=[C:30]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)[NH:29][N:28]=1
Reactant: Nc1cc(-c2ccco2)[nH]n1
Reactant: O=C1Nc2ccc(F)cc2/C1=C/O
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=CNc1cc(-c2ccco2)[nH]n1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-5-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 3-amino-5-(2-furyl)-pyrazole for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-5-fluoro-1,3-dihydro-indol-2-one (0.050 gms.) is reacted with 0.085 gms. of 3-amino-5-(2-furyl)-pyrazole by refluxing in tetrahydrofuran (1.5 mL).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[O:57]=[C:58]1[CH:62]([C:63](O)=[O:64])[CH2:61][CH2:60][N:59]1[C:66]1[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:63]([CH:62]1[CH2:61][CH2:60][N:59]([C:66]2[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=2)[C:58]1=[O:57])=[O:64]
Reactant: Cc1ccc(N2CCC(C(=O)O)C2=O)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 42.1 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.200 g; 0.865 mmol), PyBOP (0.450 g; 0.865 mmol), N,N diisopropylethylamine (0.373 mL; 2.16 mmol) and 2-oxo-1-p-tolylpyrrolidine-3-carboxylic acid (0.189 g; 0.865 mmol) in DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.144 g (42%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxo-1-p-tolylpyrrolidine-3-carboxamide as a white solid.