Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[SH:23][C:24]1[N:28]([CH3:29])[CH:27]=[N:26][N:25]=1>>[S:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[NH:13][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:23][C:24]3[N:28]([CH3:29])[CH:27]=[N:26][N:25]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cnnc1S
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Nc1nc2ccccc2s1
Product: Cn1cnnc1Sc1ccc2ncnc(Nc3nc4ccccc4s3)c2c1

Procedure:
The compound of Example 15 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, 2-amino-benzothiazole and 3-mercapto-4-methyl-1,2,4-triazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=[O:15].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:12]1[CH:11]=[C:10]([CH:14]=[O:15])[N:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccn1-c1c(Cl)cccc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 0.65 g of 1-(2,6-dichlorophenyl)-1H-pyrrole-2-carbaldehyde, and then 0.53 g of N-bromosuccinimide was added thereto. The mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, a deposited precipitate was collected by filtration to obtain 0.85 g of 4-bromo-1-(2,6-dichlorophenyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:36])=[C:21](/[CH:25]=[C:26](/[C:29]2[CH:34]=[CH:33]C(Cl)=[CH:31][CH:30]=2)\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.Cl[CH2:45][Cl:46]>>[C:1]([O:5][C:6]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=2[F:36])[C:26]([C:29]2[CH:30]=[CH:31][C:45]([Cl:46])=[CH:33][CH:34]=2)([C:27]#[N:28])[CH:9]([CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[NH:8]1)=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C/N=C/CC1CCCCC1
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1NC(CC2CCCCC2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1F
Yield: 55 %

Procedure:
In a manner similar to the method described in Example 1c, [2-cyclohexyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 59a (2.3 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (1.9 g, 6.5 mmol) prepared in Example 26a, AgF (1.7 g, 13 mmol), and triethylamine (2.6 g, 26 mmol) in dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.9 g, 55%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=2)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]=[C:6]3[CH2:8][CH2:9][CH2:10][C:5]3=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=3)[CH:3]=2)[CH2:25][CH2:26]1
Reactant: C1COCCN1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc3c2CCC3)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(N3CCOCC3)nc3c2CCC3)cc1
Yield: 24.8 %

Procedure:
Following general procedure B1, ethyl 2-(4-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.120 g, 0.36 mmol) was reacted with morpholine (0.063 g, 0.73 mmol) to afford the title compound (0.034 g, 15%) as an orange foam. MW=381.47. APCI MS m/z 382 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:22][CH3:23])=[CH:12][C:13]2[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH3:20])[C:14]=2[CH:21]=1)(=O)=O.[C:24]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[CH3:23][O:22][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:33]2[CH2:34][CH2:35][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[CH:21][C:14]2[C:15]([CH3:20])=[CH:16][C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: COc1cc2oc(=O)cc(C)c2cc1OCCCOS(C)(=O)=O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)O
Product: COc1cc2oc(=O)cc(C)c2cc1OCCCN1CCC(c2ccccc2)CC1
Yield: 77 %

Procedure:
Method B (26 h at 50° C.); starting materials: 6-[3-(methanesulfonyloxy)propoxy]-7-methoxy-4-methyl-2H-1-benzopyran-2-one (example 74) and 4-phenylpiperidine; yield 77%; fusion point 141°-143° C. (from isopropanol and ethanol). Fumarate: method E; yield 89%; fusion point 221°-223° C. (from ethanol).
Reaction SMILES: [CH2:1]([C:4]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)([CH2:7][CH:8]=[CH2:9])[CH2:5][OH:6])[CH:2]=[CH2:3].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CO>[CH2:1]([C:4]([C:10]1[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=1)([CH2:7][CH:8]=[CH2:9])[CH2:5][O:6][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:32])[F:33])=[CH:20][CH:21]=2)=[CH:30][CH:29]=1)[CH:2]=[CH2:3]
Reactant: C=CCC(CO)(CC=C)c1ccc(Br)cc1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CCC(CC=C)(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of 2-allyl-2-(4-bromo-phenyl)-pent-4-en-1-ol (from Preparation 3, Step B)(0.206 g, 0.734 mmol), 4′-trifluoromethyl-biphenyl-4-ol (0.184 g, 0.772 mmol), and triphenylphosphine (0.286 g, 1.09 mmol) in toluene (7.0 mL) is treated with 1,1′-(azodicarbonyl)-dipiperidine (0.272 g, 1.08 mmol) and stirred overnight at room temperature. The reaction is then warmed to 80° C. for 6 h, cooled to room temperature, diluted with MeOH, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% EtOAc to 50% EtOAc to provide 0.226 g, (61%) of the title compound as a yellow syrup. 1H NMR (CDCl3): δ 7.66-7.61 (m, 4H), 7.52-7.50 (m, 2H), 7.46-7.44 (m, 2H), 7.24-7.22 (m, 2H), 7.00-6.98 (m, 2H), 5.56 (ddt, J=17.1, 10.3, 7.2 Hz, 2H), 5.05-4.99 (m, 4H), 4.12 (s, 2H), 2.61 (d, J=7.4 Hz, 4H).
Reaction SMILES: [CH3:1][C:2]([CH:4](O)[CH2:5][CH2:6][C:7](=[CH2:10])[CH:8]=[CH2:9])=[CH2:3].[C:12](OCC)([O:17]CC)([O:14][CH2:15][CH3:16])[CH3:13].C(O)(=O)CC>N1C=CC=CC=1>[CH3:1]/[C:2](=[CH:4]\[CH2:5][CH2:6][C:7](=[CH2:10])[CH:8]=[CH2:9])/[CH2:3][CH2:13][C:12]([O:14][CH2:15][CH3:16])=[O:17]
Reactant: CCOC(C)(OCC)OCC
Reactant: C=CC(=C)CCC(O)C(=C)C
Solvent: c1ccncc1
Solvent: CCC(=O)O
Product: C=CC(=C)CC/C=C(\C)CCC(=O)OCC
Temperature: 135 °C
Yield: 70.5 %

Procedure:
A mixture of 2-methyl-6-methylene-1,7-octadien-3-ol (34 g, 0.224 M), triethyl orthoacetate (80 g, 0.5 M) and propionic acid (1 ml) is heated at 135° C. (bath temperature) under nitrogen for four hours. The resulting mixture is cooled to room temperature and treated with pyridine (1 ml). Most of the excess reagent is removed in vacuo (high vacuum pump) and the residue is purified by column chromatography on silica gel (300 g) with 5% ether in petroleum ether, to give ethyl 4-methyl-8-methylene-(E)-4,9-decadienoate (35 g, 70%) as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:21][CH:22]([CH3:26])[C:23](Cl)=[O:24].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:23](=[O:24])[CH:22]([CH3:26])[CH3:21])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)cc(-c2nc(NC(=O)C(C)C)sc2-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 82.2 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.53 mmol) in N,N-dimethylacetamide (20 mL) was added 2-methylpropionyl chloride (0.20 g, 1.91 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.52 g, yield 83%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1>>[C:4]([CH2:3][CH2:2][NH:1][C:7](=[O:13])/[CH:8]=[CH:9]\[C:10]([OH:12])=[O:11])([OH:6])=[O:5]
Reactant: NCCC(=O)O
Reactant: O=C1C=CC(=O)O1
Product: O=C(O)/C=C\C(=O)NCCC(=O)O
Yield: 68 %

Procedure:
In the same manner, equimolar amounts of 3-aminopropionic acid and maleic anhydride are reacted to produce N-carboxyethylmaleamic acid (M.P. 150°-152° C.) in 68% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[NH:8][N:7]=2)=[CH:2]1.P(Cl)(Cl)([Cl:19])=O>ClC(Cl)C>[Cl:19][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=1
Reactant: O=c1[nH]nc(-c2ccsc2)c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: Clc1nnc(-c2ccsc2)c2ccccc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
500 mg of 4-(3-thienyl)-1-phthalazinone and 3 ml of phosphorus oxychloride were dissolved in 6 ml of dichloroethane, and the solution was stirred at 100° C. for 4 hours. The reaction solution was distilled off, and a 1-N aqueous NaOH solution was added thereto under cooling with ice. The solution was extracted with chloroform and dried over magnesium sulfide. The solvent was then distilled off, thereby obtaining 515 mg of 1-chloro-4-(3-thienyl)phthalazine.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[O:43][C:44]3[CH:54]=[C:53]([N:55]([CH3:60])[S:56]([CH3:59])(=[O:58])=[O:57])[C:52](B4OC(C)(C)C(C)(C)O4)=[CH:51][C:45]=3[C:46]=2[C:47]([NH:49][CH3:50])=[O:48])=[CH:38][CH:37]=1.[CH2:70]([O:77][C:78]1[C:79]([C:85]([O:87][CH3:88])=[O:86])=[N:80][C:81](Br)=[CH:82][CH:83]=1)[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:70]([O:77][C:78]1[C:79]([C:85]([O:87][CH3:88])=[O:86])=[N:80][C:81]([C:52]2[C:53]([N:55]([CH3:60])[S:56]([CH3:59])(=[O:58])=[O:57])=[CH:54][C:44]3[O:43][C:42]([C:39]4[CH:38]=[CH:37][C:36]([F:35])=[CH:41][CH:40]=4)=[C:46]([C:47](=[O:48])[NH:49][CH3:50])[C:45]=3[CH:51]=2)=[CH:82][CH:83]=1)[C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1
Reactant: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)OC)n3)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Pd2(dba)3 (45 mg, 0.05 mmol) and X-phos (48 mg, 0.1 mmol) were added to a mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (500 mg, 1 mmol), methyl 3-(benzyloxy)-6-bromopicolinate (350 mg, 1.1 mmol) and K3PO4.3H2O (798 mg, 3 mmol) in 1,4-dioxane/H2O (5 mL/0.5 mL) under N2. The mixture was stirred at 80° C. for 8 h, and after being filtered through celite, the filtrate was concentrated in vacuo, diluted with water and extracted with EtOAc. The residue was purified by column chromatography (DCM:EtOAc=40:1 to 10:1) to obtain methyl 3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinate (540 mg, yield: 88%). 1H-NMR (CDCl3, 400 MHz) δ 7.88˜8.04 (m, 3H), 7.70 (d, J=8.8 Hz, 1H), 7.62 (s, 1H), 7.45˜7.56 (m, 3H), 7.41 (t, J=7.2 Hz, 2H), 7.32˜7.38 (m, 1H), 7.20 (t, J=8.4 Hz, 2H), 5.90 (d, J=4.0 Hz, 1H), 5.27 (s, 2H), 3.97 (s, 3H), 3.22 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 618.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.C(OCC)C>CO.C(OCC)(=O)C.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 18 h
Yield: 89.6 %

Procedure:
To a solution of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (I1) (1.90 g, 5.63 mmol) in methanol (20 mL) and ethyl acetate (80 mL) was added 10% Pd/C (0.500 g). The mixture was evacuated and backfilled three times with hydrogen gas then stirred under a hydrogen atmosphere for 18 hours. The crude reaction mixture was filtered through a plug of Celite, washing with ethyl acetate and the filtrate evaporated in vacuo then dried under high vacuum to give a dark red viscous oil. The oil was suspended in a 2:1 solution of diethyl ether and petroleum ether (15 mL) and sonicated for 3 minutes. The resulting mixture was evaporated in vacuo and dried under high vacuum to give the title compound (I2) (1.55 g, 89%) as a dark red solid; 1H NMR (300 MHz, d6-DMSO) δ 1.47 (s, 9H), 2.97 (t, 4H, J=4.7 Hz), 3.57 (t, 4H, J=4.7 Hz), 3.83 (s, 3H), 6.40 (dd, 1H, J=8.3, 2.1 Hz), 6.50 (d, 1H, J=2.0 Hz) and 6.64 (d, 1H, J=8.3 Hz). LCMS Method B: rt 5.02 min; m/z 308.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:23])=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[N:6]([CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[C:5]2=[O:22].CC(O)C.Cl.CO>O1CCOCC1.[Pd]>[NH2:1][C:2]1[C:3]([Cl:23])=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:14])[N:6]([CH:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)[C:5]2=[O:22]
Reactant: CN1CCC(N2C(=O)c3cc([N+](=O)[O-])c(N)c(Cl)c3C2=O)CC1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCC(N2C(=O)c3cc(N)c(N)c(Cl)c3C2=O)CC1
Reaction time: 1.5 h
Yield: 6 %

Procedure:
To a mixture of 5-amino-4-chloro-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione (1.35 g, not pure) and 10% Pd/C (500 mg) was added 2-propanol (20 mL), HCl in dioxane (4 M, 0.1 mL) and then MeOH (230 mL). After it was stirred under atmospheric hydrogen for 1.5 h, the reaction mixture was filtered over Celite. The filtrate was concentrated, diluted with 50% DCM in MeOH, basified with aqueous NH4OH solution (28%) and evaporated. Chromatography of the mixture with mixed solvent of CH2Cl2/MeOH/28% aqueous NH4OH (50:10:1) afforded the title compound (186 mg, 6% for 2 steps). 1H NMR (DMSO-d6) δ 1.51 (m, 2H), 1.90 (m, 2H), 2.29 (m, 2H), 2.81 (m, 2H), 3.80 (m, 1H), 5.61 (br s, 2H, NH2), 5.93 (br s, 2H, NH2), 6.82 (s, 1H, ArH); ESI-MS m/z 309.4 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][NH2:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][NH:24][C:13]([C@@H:9]1[CH:10]=[CH:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CC=C[C@H]1C(=O)NOCc1ccccc1

Procedure:
(S)-tert-Butyl 2-(benzyloxycarbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate is prepared from (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (Boc-3,4-dehydro-proline) and O-benzylhydroxylamine following Method G. 1H NMR (300 MHz, CHCl3) δ 9.38 (s, 0.5H), 8.46 (s, 0.5H), 7.52-7.22 (m, 5H), 6.01-5.77 (m, 2H), 5.04-4.79 (m, 3H), 4.38-3.99 (m, 2H), 1.43 (s, 9).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O-:22].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([O:22][CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)n2)CC1
Reactant: C[O-]
Agent: [Na+]
Product: COc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 mmol of 4-(4-Chloro-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester [example 4.11 a)] was dissolved in a solution of sodium methanolate (prepared by dissolving 1 mmol of sodium in 5 ml of methanol). The mixture was stirred at room temperature for 1 hour, concentrated and the title compound purified by recrystallisation from ethyl acetate/cyclohexane. MS (m/e): 296.3 (MH+, 100%)
Reaction SMILES: [CH3:1][C:2]([F:13])([C:6]([F:12])([F:11])[C:7](F)([F:9])[F:8])[CH:3](Cl)[F:4].CC(C#C)=C>>[CH3:1][C:2]([F:13])([C:6]([F:11])([F:12])[CH:7]([F:8])[F:9])[CH2:3][F:4]
Reactant: CC(F)(C(F)Cl)C(F)(F)C(F)(F)F
Agent: C#CC(=C)C
Product: CC(F)(CF)C(F)(F)C(F)F

Procedure:
As another example, 2-methyl-l-chloro-1,2,3,3,4,4,4-heptafluorobutane may be prepared by fluorinating commercially available 2-methyl-l-buten-3-yne to form 2-methyl-1,2,3,3,4,4-hexafluorobutane which may then be dehydrohalogenated to form 2-methyl-1,3,4,4-tetrafluoro-1,3-butadiene. The 2-methyl-1,3,4,4-tetrafluoro-1,3-butadiene may then be fluorinated to form 2-methyl-1,1,2,3,3,4,4,4-octafluorobutane which may then be dehalogenated to form 2-methyl-1,3,3,4,4,4-hexafluoro-l-butene. The 2-methyl-1,3,3,4,4,4-hexafluoro-1-butene may then be chlorofluorinated to form 2-methyl-1-chloro-1,2,3,3,4,4,4-heptafluorobutane.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17].[C:19](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:19][O:17][C:16](=[O:18])[CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Br:8]
Reactant: CC(=O)O
Reactant: O=C(O)Cc1ccccc1Br
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.349 mL, 0.698 mmol) was added to a solution of (2-bromo-phenyl)acetic acid (50 mg, 0.233 mmol) in methanol (0.4 mL) and toluene (2 mL), and the mixture was stirred at room temperature for five minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (53 mg, 99%).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(Cl)(Cl)Cl.[Br:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])O.[Na+]>O.N1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]([S:18]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)COS(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 108.1 %

Procedure:
Under cooling in an ice bath, 2,2-dimethyl-1-propanol (1.55 g) was added to a chloroform (20 mL) solution that contained 3-bromobenzenesulfonyl chloride (3.00 g) and pyridine (1.86 g), and the obtained solution was then stirred at a room temperature for 60 hours. Thereafter, water and a saturated sodium hydrogencarbonate aqueous solution were added to the reaction solution, and the obtained mixture was then extracted with chloroform. The organic layer was washed with a saturated saline, and was then dried over anhydrous sodium sulfate, followed by vacuum concentration. The obtained solid was washed with n-hexane, so as to obtain the title compound (3.90 g) in the form of a colorless solid.
Reaction SMILES: [C:1]1([C:7]2([O:20][C:21]3([CH:24]([OH:27])CO)[CH2:23][CH2:22]3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.O.CCOC(C)=O>[C:1]1([C:7]2([O:20][C:21]3([CH:24]=[O:27])[CH2:22][CH2:23]3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC(O)C1(OC2(c3ccccc3)c3ccccc3-c3ccccc32)CC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=CC1(OC2(c3ccccc3)c3ccccc3-c3ccccc32)CC1

Procedure:
A suspension of 2-[1-(9-Phenyl-9-fluorenoxy)cyclopropyl]-1,2-dihydroxyethane in THF:H2O is treated with NalO4 (1.1 eq). The resulting suspension is stirred at room temperature for 4h and then diluted with H2O and EtOAc. The EtOAc extract is washed consecutively with 10% aq sodium thiosulfate solution and then brine. The EtOAc layer is dried (Na2SO4) and concentrated in vacuo. The crude product is purified by filtration through a short pad of silica gel.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[C:6]([CH3:8])[S:5][C:4]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:7]=[C:6]([CH3:8])[S:5][C:4]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1cc(Cl)c(C2CC(=O)c3c(C)ccnc3C2)s1
Agent: Cl
Solvent: CCO
Product: Cc1cc(Cl)c(C2CC(=NNC(=N)N)c3c(C)ccnc3C2)s1
Temperature: 110 °C
Reaction time: 3 h
Yield: 199.9 %

Procedure:
To a mixture of 7-(3-chloro-5-methylthiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (1 g) and aminoguanidine hydrochloride (0.366 g) were added ethanol (12 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 110° C. (bath temperature) for 3 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(3-chloro-5-methylthiophen-2-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 172) (1.17 g) as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=1)[C@:3]([C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[F:13])([OH:5])[CH3:4].N([C@H](C1C=NC=C(Br)C=1)[C@@](C1C=C(F)C=CC=1F)(O)C)=[N+]=[N-]>>[NH2:1][C@H:2]([C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=1)[C@@:3]([C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[F:13])([OH:5])[CH3:4]
Reactant: C[C@](O)(c1cc(F)ccc1F)[C@H](N)c1cncc(Br)c1
Agent: C[C@@](O)(c1cc(F)ccc1F)[C@H](N=[N+]=[N-])c1cncc(Br)c1
Product: C[C@@](O)(c1cc(F)ccc1F)[C@H](N)c1cncc(Br)c1

Procedure:
Prepared according to the same procedure as (1R,2S)-1-amino-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol, starting with (1R,2R)-1-azido-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J=2.1 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.03 (t, J=1.8 Hz, 1H), 7.38-7.31 (m, 1H), 7.23-7.10 (m, 2H), 5.60 (s, 1H), 4.18 (s, 1H), 1.91 (br. s., 2H), 1.24 (d, J=1.2 Hz, 3H), Mass spec.: 343.1 (MH)+.