Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:8]2[C:13]([C:14]3[C:32]([F:33])=[CH:31][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][C:15]=3[F:34])=[C:12](O)[N:11]=[C:10]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:44])=O.N1C(C)=CC=CC=1C>>[Cl:44][C:12]1[N:11]=[C:10]([C:36]2[CH:41]=[N:40][CH:39]=[CH:38][N:37]=2)[N:9]=[C:8]([CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]=1[C:14]1[C:32]([F:33])=[CH:31][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][C:15]=1[F:34]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(CCCOc1cc(F)c(-c2c(O)nc(-c3cnccn3)nc2C2CCCCCC2)c(F)c1)C(=O)OC(C)(C)C
Solvent: Cc1cccc(C)n1
Product: CN(CCCOc1cc(F)c(-c2c(Cl)nc(-c3cnccn3)nc2C2CCCCCC2)c(F)c1)C(=O)OC(C)(C)C
Temperature: 110 °C

Procedure:
To tert-butyl {3-[4-(4-cycloheptyl-6-hydroxy-2-pyrazin-2-ylpyrimidin-5-yl)-3,5-difluorophenoxy]propyl}methylcarbamate (130 mg, 0.23 mmol) is added 2.0 mL of phosphorous oxychloride and 1.0 mL of 2,6-lutidine, and the mixture is heated at 110° C. for 12 h. The excess phosphorous oxychloride is removed in vaccuo, and the resulting residue is chromatographed over silica gel, eluting with 30% ethyl acetate in hexanes. Concentration provides tert-butyl {3-[4-(6-chloro-4-cycloheptyl-2-pyrazin-2-ylpyrimidin-5-yl)-3,5-difluorophenoxy]propyl}methylcarbamate as a light yellow semi-solid (23 mg). MS: m/z 588.0 (M+H). This product is dissolved in 2 mL of methylene chloride, and 2.3 mL of trifluoroacetic acid is added. The mixture is stirred at 40° C. for 20 h, and concentrated in vaccuo, yielding N-{3-[4-(4-chloro-6-cycloheptyl-2-pyrazin-2-ylpyrimidin-5-yl)-3,5-difluorophenoxy]propyl}-N-methylamine as a trifluoroacetic acid salt as a light yellow semi-solid (24 mg). MS: m/z 488.2 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: Nc1nnc(-c2ccc(Cl)c(Cl)c2)c(-c2ccccc2)n1
Yield: 54.8 %

Procedure:
6-(3,4-Dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (52 mg, 54%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3,4-dichlorophenylboronic acid (65.5 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=2[CH3:30])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=4[CH3:30])[CH2:20][CH2:19]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(Cl)cc3)CC2)CC1

Procedure:
Example 89 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.40–7.32 (m, 7H), 7.08 (d, 1H, J=8.4 Hz), 5.70 (br s, 1H), 3.27 (dd, 2H, J=6.4, 12.4 Hz), 2.88 (d, 2H, J=11.6 Hz), 2.64 (m, 1H), 2.53 (m, 1H), 2.31 (t, 2H, J=6.8 Hz), 2.28 (s, 3H), 1.99 (dt, 2H, J=2.8, 11.2 Hz), 1.67–1.60 (m, 8H), 1.27 (d, 6H, J=6.8 Hz), 1.03 (dd, 2H, J=4.0, 6.8 Hz); ESMS m/e: 496.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9]Br)=[CH:4][N:3]=1.[CH3:11][S-:12].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][S:12][CH3:11])=[CH:4][N:3]=1
Reactant: Fc1cc(CBr)cnc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSCc1cnc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
A solution of 2-chloro-3-fluoro-5-bromomethylpyridine (3.7 g, 16.5 mmol) in ethanol (40 mL) was treated with sodium thiomethoxide solid (2.31 g, 33 mmol) portionwise at 0° C. After the addition was over, the mixture was stirred at room temperature overnight. Most of the solvent ethanol was removed under reduced pressure and the residue was re-taken into dichloromethane. Brine solution was added and two phases mixed and separated. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified on silica gel using 8% EtOAc in hexane as eluent to give 2.04 g of the desired 2-chloro-3-fluoro-5-methylthiomethylpyridine in 65% yield. GC-MS calcd. for C7H7ClFNS: 191.66. Found: 191.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=1)=[O:3].[Se](=O)=[O:16]>>[F:14][C:11]([F:12])([F:13])[O:10][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[O:16])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[Se]=O
Reactant: CC(=O)c1cccc(OC(F)(F)F)c1
Product: O=CC(=O)c1cccc(OC(F)(F)F)c1

Procedure:
3-(Trifluoromethoxy)acetophenone (2 g, 9.80 mmol) was reacted with selenium dioxide (1.63 g, 14.7 mmol) using the method described in Example 1 to give crude (3-trifluoromethoxyphenyl)oxoacetaldehyde as a yellow oil: m/z (ES+) 219.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]2[N:38]=[C:37](Cl)[N:36]=[C:35]([NH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]3[CH2:50][C:49]([CH3:52])([CH3:51])[N:48]([O:53][CH3:54])[C:47]([CH3:56])([CH3:55])[CH2:46]3)[N:34]=2)[N:3]=1.[CH2:57]([CH2:59][NH2:60])[OH:58]>>[OH:58][CH2:57][CH2:59][NH:60][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]2[N:38]=[C:37]([NH:60][CH2:59][CH2:57][OH:58])[N:36]=[C:35]([NH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]3[CH2:50][C:49]([CH3:52])([CH3:51])[N:48]([O:53][CH3:54])[C:47]([CH3:56])([CH3:55])[CH2:46]3)[N:34]=2)[N:3]=1
Reactant: NCCO
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCCCNc3nc(Cl)nc(NCCCCC4CC(C)(C)N(OC)C(C)(C)C4)n3)n2)CC1(C)C
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCCCNc3nc(NCCO)nc(NCCCCC4CC(C)(C)N(OC)C(C)(C)C4)n3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of N,N'-bis{2-chloro-4-[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl}-1,6-hexanediamine and ethanolamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[NH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:36]>>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH:50]([NH:49][C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:51][CH2:52]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CC[C@@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CC[C@@]3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using (R)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]O)=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]1([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][O:17][C:16]([C@@H:11]3[CH2:12][S:13][CH2:14][CH2:15][N:10]3[S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=3)(=[O:9])=[O:8])=[O:18])=[CH:32][CH:33]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: OCc1ccc(-c2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 103.4 %

Procedure:
0.200 g (0.6 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.184 g (1.0 mmol) of 4-phenylbenzyl alcohol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:9) to obtain the product as a oil (0.29 g).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=1)[C:9]([OH:11])=O)[CH2:4][CH3:5])[CH3:2].[CH2:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([CH3:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:22]([NH:24]O)=[NH:23])[CH3:18]>>[CH2:17]([C:19]1[CH:20]=[C:21]([C:22]2[N:24]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[CH:7]=3)[O:11][N:23]=2)[CH:26]=[C:27]([CH3:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:31])=[O:32])[CH3:18]
Reactant: CCC(CC)c1cc(C(=O)O)cc(OC)n1
Reactant: CCc1cc(C(=N)NO)cc(C)c1NS(C)(=O)=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1NS(C)(=O)=O
Yield: 36.6 %

Procedure:
The title compound (24 mg) is prepared in analogy to Example 11 starting from 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid (32 mg, 143 μmol) and 3-ethyl-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine (40 mg, 150 mmol); LC-MS**: tR=0.91 min, [M+H]+=459.09; 1H NMR (CDCl3): δ0.85 (t, J=7.3 Hz, 6H), 1.36 (t, J=7.3 Hz, 3H), 1.69-1.89 (m, 4H), 2.56 (s, 3H), 2.57-2.65 (m, 1H), 2.93 (q, J=7.5 Hz, 2H), 3.18 (s, 3H), 4.02 (s, 3H), 5.92 (s, 1H), 7.33 (s, 1H), 7.44 (s, 1H), 7.97 (s, 1H), 7.99 (s, 1H).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:7]=2[N:6]([CH2:17][C:18]([OH:20])=[O:19])[C:5]1=[O:21])=[N+]=[N-].Cl>C(O)C.O.[Pd]>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:7]=2[N:6]([CH2:17][C:18]([OH:20])=[O:19])[C:5]1=[O:21]
Reactant: COc1ccc2c(c1)N(CC(=O)O)C(=O)C(N=[N+]=[N-])CC2
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)N(CC(=O)O)C(=O)C(N)CC2
Reaction time: 3 h

Procedure:
A solution of 3-azido-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (11 g) in a mixture of ethanol (250 ml) and water (50 ml) was hydrogenated for 3 hours on a Parr shaker at 3 atmospheres pressure and room temperature using 10% Pd-C (0.5 g) as catalyst. 2N Hydrochloric acid (50 ml) was added, and the catalyst was filtered off. The solvent was removed at reduced pressure, and the residue dissolved in a mixture of water (50 ml) and ethanol (50 ml). Propylene oxide (25 ml) was added and the mixture was stirred for 1 hour. The solvents were removed under reduced pressure to give 3-amino-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one, m.p. >300°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]1CCCC1=O.CN>O>[CH3:15][NH:16][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CN1CCCC1=O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: CN
Solvent: O
Product: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.09 g of 4-fluoro-3-nitrobenzo trifluoride and 20 ml of N-methylpyrrolidone was added 2.33 g of a 40% methylamine aqueous solution under ice cool, and the mixture was heated up to room temperature and stirred for 1 hour. Water was poured, and the deposited precipitate was filtrated, then, washed with water, then, dried under reduced pressure to obtain 2.0 g of N-methyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([NH:12][CH2:13][C:14]([O:16]C)=O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[CH2:3]([C@@H:2]1[C:10](=[O:11])[NH:12][CH2:13][C:14](=[O:16])[NH:1]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CNC(=O)[C@H](N)Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CNC(=O)[C@@H](Cc2ccccc2)N1
Temperature: 0 °C

Procedure:
The crude product D-Phe-Gly-OMe (6 g, 25 mmol) was powdered and then dispersed in 100 ml toluene and heated at reflux overnight. The reaction flask was cooled to 0° C. and the solid product (3.50 9, 69%) was collected by filtration: m.p. 256°-257° C.; DCI-NH3 -MS, m/z (relative intensity), 222 (MNH4+, 100%), 205 (MH+, 31%);
Reaction SMILES: C(OC1C=C(C(F)=CC=1Cl)[NH2:8])C=C.[CH2:14]1[CH:19]2[C:20](O[C:23](=[O:24])[CH:18]2[CH2:17][CH:16]=[CH:15]1)=[O:21].C(O)(=O)C>O>[C:23]1(=[O:24])[NH:8][C:20](=[O:21])[C:19]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1=2
Reactant: C=CCOc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2CC=CCC12
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C2=C1CCCC2
Temperature: 25 °C

Procedure:
A mixture of 9.0 g of 19A, 6.8 g of THPA and 100 mL of glacial acetic acid was heated at reflux temperature for 4 hours. The resulting mixture was cooled to room temperature, poured into 450 mL of water and extracted with ether. The extract phase was washed with water, dried (Na2SO4), and filtered, and the solvent was evaporated from the filtrate. The residue was flash-chromatographed on silica gel, with a 15:85 v:v mixture of ethyl acetate and hexane as eluent, to give N-(3-allyloxy)-4-chloro-6-fluorophenyl)-3,4,5,6-tetrahydrophthalimide (19B), as an orange oil.
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[OH:23]>>[OH:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[NH:16][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:12]=1)=[O:15]
Reactant: O=C(O)c1cccc(C2CCCCC2)n1
Reactant: NC1CCCCC1O
Product: O=C(NC1CCCCC1O)c1cccc(C2CCCCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclohexyl-pyridine-2-carboxylic acid (Example 7 b) and 2-aminocyclohexanol (CAN 6850-38-0) as starting materials, MS (EI): m/e=303.2 [M+H]+.
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:11])[C:9]#[CH:10]>C1(C)C=CC=CC=1>[CH2:8]([NH:11][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[C:9]#[CH:10]
Reactant: C#CCN
Reactant: COCC(Cl)C=O
Solvent: Cc1ccccc1
Product: C#CCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Propargylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-propargylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[S-:8].[Na+].Cl[C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[S:8][C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: Fc1cncc(F)c1[S-]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: [Na+]
Product: COC(=O)c1cc([N+](=O)[O-])c(Sc2c(F)cncc2F)s1
Yield: 66.9 %

Procedure:
Prepared according to the procedure described for example 18, sodium 3,5-difluoropyridine-4-thiolate (529 mg, 3.6 mmol) reacted with methyl 5-chloro-4-nitro-thiophene-2-carboxylate (800 mg, 3.6 mmol) to afford the titled product (800 mg, 67% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.91 (2H, s), 8.18 (1H, s), 3.85 (3H, s). MS m/z: 333.04 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]/[CH:15]=[CH:16]/[OH:17])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[N:9]=2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[CH:16]=[O:17])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C/C=C/O
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/C=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl](2E)-propen-1-ol-(5 g) was dissolved in toluene (50 ml) at 25° C. and manganese dioxide (20 g) was added to it. The reaction mixture was stirred for 5 h at 25° C. After completion of the reaction, reaction mixture was filtered through hyflo and toluene was evaporated under reduced pressure at 40° C. to obtain the product as a semi solid. The product was further crystallized from hexane-ethyl acetate (20 ml, 9:1 v/v) (Yield: 4.8 g).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[N:9]2[C:10](=[O:13])[C:11]=1[C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(N=[N+]=[N-])c1nc2scc(C(F)(F)F)n2c(=O)c1Br
Product: CC(N=[N+]=[N-])c1nc2scc(C(F)(F)F)n2c(=O)c1-c1cccc(F)c1
Yield: 29 %

Procedure:
The desired compound was prepared according to the procedure of Example 8, step 5, using 7-(1-azidoethyl)-6-bromo-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one and (3-fluorophenyl)boronic acid as the starting materials in 29% yield. LCMS for C15H10F4N5OS (M+H)+: m/z=383.9.
Reaction SMILES: [O:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH:3]=[C:2]1[C:13]([OH:15])=O.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[O:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH:3]=[C:2]1[C:13]([Cl:18])=[O:15]
Reactant: O=C(O)c1cc2[nH]c3ccccc3c2o1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1cc2[nH]c3ccccc3c2o1

Procedure:
To ethyl furo[3,2-b]indole-2-carboxylate (10 g), 10% aqueous sodium hydroxide solution (100 ml) was added, then the mixture was stirred for an hour at 60° C. The resulting solution was acidified with hydrochloric acid, and the precipitate formed was collected by filtration to give furo[3,2-b]indole-2-carboxylic acid (8.5 g). To furo[3,2-b]-indole-2-carboxylic acid (8.5 g), thionyl chloride (40 ml) and benzene (50 ml) were added, the resulting solution was refluxed for 5 hours, and the excess amounts of thionyl chloride and the benzene were evaporated to give furo[3,2-b]indole-2-carbonyl chloride (7.1 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH3:17][C@H:18]1[CH2:26][C:25]2[C:20](=[CH:21][C:22](C)=[CH:23][CH:24]=2)[C@@H:19]1[NH2:28].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([NH:28][C@H:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:26][CH2:18][CH2:17]2)[N:7]=1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: Cc1ccc2c(c1)[C@H](N)[C@@H](C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1c(N[C@@H]2CCCc3ccccc32)nc(N)nc1-c1ccccc1
Yield: 70.4 %

Procedure:
A mixture of 0.40 g (1.21 mmol) of 2-amino-4-chloro-6-phenylpyrimidine-5-carbonitrile (crude mixture as precursor, ca. 70% purity), 0.27 g (1.82 mmol) of (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine and 0.34 g (2.42 mmol) of potassium carbonate is heated in 1 ml of N-methylpyrrolidone as solvent at 150° C. for 60 minutes in a microwave appliance (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture is absorbed on silica gel and, following column chromatographic separation, 0.291 g of 2-amino-4-phenyl-6-[(1R)-1,2,3,4-tetrahydronaphthalen-1-ylamino]pyrimidine-5-carbonitrile is obtained (solid, 67% yield, 95% purity).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[C:17]2[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)=[O:5])[CH3:2]>[Pd].C(O)C.O1CCOCC1>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)COc1ccnc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)COc1ccnc2c(N)cccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
A mixture of 4-ethoxycarbonylmethoxy-8-nitroquinoline (404 mg) and 10% palladium on carbon in ethanol (5 ml) and dioxane (5 ml) was stirred for 5 hours at ambient temperature under hydrogen atmosphere. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was pulverized with diethyl ether to give 8-amino-4-(ethoxycarbonylmethoxy)quinoline (234 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C:12]1[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:24][O:25][CH2:26][CH2:27]Br>CN(C=O)C>[CH3:24][O:25][CH2:26][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C:12]1[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=1
Reactant: CC(=O)Nc1ccc(O)c(-c2ccnn2C)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(NC(C)=O)cc1-c1ccnn1C
Temperature: 110 °C
Yield: 85 %

Procedure:
A mixture of N-(4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl)acetamide (1.16 g, 5.00 mmol), cesium carbonate (3.26 g, 10.00 mmol), and 2-bromoethyl methyl ether (0.666 mL, 7.00 mmol) in 10 mL of DMF was heated to 110° C. for 15 minutes under microwave irradiation in a heavy-walled sealed tube. The solvent was evaporated under reduced pressure, and the residue was taken up in water and extracted three times with dichloromethane. The combined extracts were dried with sodium sulfate, filtered, and evaporated to dryness to afford the title compound (1.23 g, 85.0% yield) as a tan solid which was used without further purification. LCMS m/z (%) 290.1 (M+H, 100%). 1H NMR (400 MHz, DMSO-d6) δ 2.01 (s, 3H) 3.22 (s, 3H) 3.55-3.60 (m, 2H) 3.65 (s, 3H) 4.06-4.12 (m, 2H) 6.22 (d, J=1.77 Hz, 1H) 7.10 (d, J=9.09 Hz, 1H) 7.43 (d, J=2.02 Hz, 1H) 7.49 (d, J=2.78 Hz, 1H) 7.59 (dd, J=8.97, 2.65 Hz, 1H) 9.90 (s, 1H).