Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].C(N(C(C)C)CC)(C)C.[CH2:30]([C:37]1[S:41][C:40]([NH2:42])=[N:39][N:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN(C=O)C>ClCCl>[CH2:30]([C:37]1[S:41][C:40]([NH:42][C:16]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]3)=[CH:20][CH:19]=2)=[O:18])=[N:39][N:38]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Nc1nnc(Cc2ccccc2)s1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccc(C(=O)O)cc2)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1CC[C@H](Oc2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.301 g of trans-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid (1.08 mmol, 1 eq.) is placed in 5 mL of dichloromethane at room temperature. 0.36 mL of diisopropylethylamine (2.16 mmol, 2 eq.), 0.604 g of bromotris-pyrrolidinophosphonium hexafluorophosphonate (1.30 mmol, 1.2 eq.) and 0.207 g of 5-benzyl-1,3,4-thiadiazol-2-amine (1.08 mmol, 1 eq.) are successively added. 2 mL of DMF are then added. The reaction mixture is stirred for 18 hours at room temperature. 0.1 mL of diisopropylethylamine (0.6 mmol, 0.55 eq.), 0.2 g of bromotris-pyrrolidinophosphonium hexafluorophosphonate (0.43 mmol, 0.4 eq.) and 0.05 g of 5-benzyl-1,3,4-thiadiazol-2-amine (0.26 mmol, 0.24 eq.) are added. The reaction medium is stirred at 50° C. for 6 hours, diluted in dichloromethane, and washed with water and with saturated aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and concentrated, and the residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 10% to 70%. The fractions of interest are evaporated. The solid obtained is triturated in ethanol to give 0.128 g of methyl trans-4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenoxy]cyclohexanecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.N1CCCN2CCCCCC=12.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33]>C1COCC1.O>[CH3:30][N:31]([CH3:35])[C:32]([N:16]1[CH:15]=[C:14]([C:3]2[N:4]=[C:5]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[S:6][C:2]=2[CH3:1])[CH:18]=[N:17]1)=[O:33]
Reactant: Cc1sc(Nc2ccccn2)nc1-c1cn[nH]c1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(Nc2ccccn2)nc1-c1cnn(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59 %

Procedure:
According to Scheme 19: A solution of 5-methyl-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine (0.39 mmol, 100 mg), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.39 mmol, 58 μL) and dimethylcarbamic chloride (0.39 mmol, 36 μL) in THF (5 mL) was stirred at room temperature during one day. Then, 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.39 mmol, 58 μL) and dimethylcarbamic chloride (0.39 mmol, 36 μL) were added and the mixture was stirred at room temperature during 3 days. The solution was diluted with water (50 mL) and the aqueous layer was extracted twice with DCM. The organic phases were dried over MgSO4, were filtered and were concentrated to afford a beige solid. The crude compound was purified by flash chromatography with silica gel using DCM/MeOH (98:2) as eluent to afford N,N-dimethyl-4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazole-1-carboxamide (0.23 mmol, 76 mg, 60%) as a beige solid.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([N:14]4[C:18]([CH3:19])=[N:17][N:16]([CH:20]([CH3:22])[CH3:21])[C:15]4=[O:23])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.IC1C=CC2C3N=C(N4C(C)=NN(C(C)C)C4=O)SC=3CCOC=2C=1.[CH3:51][C:52]([OH:69])([CH3:68])[CH2:53][N:54]1[CH:58]=[C:57](B2OC(C)(C)C(C)(C)O2)[CH:56]=[N:55]1>>[OH:69][C:52]([CH3:68])([CH3:51])[CH2:53][N:54]1[CH:58]=[C:57]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([N:14]5[C:18]([CH3:19])=[N:17][N:16]([CH:20]([CH3:22])[CH3:21])[C:15]5=[O:23])[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:56]=[N:55]1
Reactant: Cc1nn(C(C)C)c(=O)n1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cc1nn(C(C)C)c(=O)n1-c1nc2c(s1)CCOc1cc(I)ccc1-2
Product: Cc1nn(C(C)C)c(=O)n1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Following the procedure for 473, a mixture of 4-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one and 4-(8-iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one and 2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol were reacted to give 474 isolated as a white solid (34 mg, 59%). LCMS: RT=4.79 min, [M+H]+=481. 1H NMR δ (ppm) (DMSO-d6): 8.15 (1H, d, J=8.26 Hz), 8.08 (1H, s), 7.87 (1H, d, J=0.74 Hz), 7.33 (1H, dd, J=8.26, 1.84 Hz), 7.22 (1H, d, J=1.82 Hz), 4.68 (1H, s), 4.38-4.28 (3H, m), 3.99 (2H, s), 3.28 (2H, m), 2.67 (3H, s), 1.29 (6H, t, J=6.68 Hz), 1.05 (6H, s)
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[O:36])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: COc1ccc(N=C=O)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: COc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) and 4-methoxyphenylisocyanate (0.21 g, 1.4 mmol) in acetonitrile (30 mL) at 0° C. The mixture was stirred at ambient temperature for 2 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-methoxy-phenyl)-urea as a white solid (0.48 g, 84% yield); mp 255-257° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.39 (99.34%); 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H, CHH), 2.29-2.47 (m, 1H, CHH), 2.54-2.66 (m, 1H, CHH), 2.83-2.99 (m, 1H, CHH), 3.69 (s, 3H, CH3), 4.30 (d, 1H, CHH), 4.36-4.50 (m, 3H, CH2 and CHH), 5.11 (dd, 1H, CH), 6.65 (t, 1H, NH), 6.81 (d, J=8.9 Hz, 2H, Ar), 7.31 (d, 2H, Ar), 7.44 (d, 1H, Ar), 7.51 (s, 1H, Ar), 7.69 (d, 1H, Ar), 8.44 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 8.60, 22.49, 31.20, 42.79, 45.69, 47.10, 51.56, 55.12, 113.86, 119.50, 121.85, 122.91, 126.88, 130.25, 133.50, 142.36, 145.03, 153.98, 155.45, 167.96, 170.99, 172.86; LCMS: MH=423; Anal. Calcd for C22H22N4O5+0.1H2O: C, 62.55; H, 5.25; N, 13.26. Found: C, 62.12; H, 5.36; N, 13.21.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=O>>[CH:34]([N:8]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:38][CH:37]=1)[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1)([CH3:36])[CH3:35]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: O=C(CCl)N1CCOCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCOCC3)cc2)C(C)C)c1
Yield: 71.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-morpholin-4-ylethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (22 mg) was obtained.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:12])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].[C-:13]#[N:14].[Na+]>CS(C)=O>[C:13]([CH2:2][C@@H:3]([OH:12])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6])#[N:14]
Reactant: CCCCOC(=O)C[C@H](O)CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCOC(=O)C[C@H](O)CC#N
Temperature: 65 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
The resulting compound was cyanogenated in the same manner as in Example 1-(2). That is, 58.5 g (0.3 mol) of n-butyl (S)-(-)-4-chloro-3-hydroxybutyrate was dissolved in 180 ml of dimethyl sulfoxide, and 67.5 ml of an aqueous solution containing 16.7 g (0.34 mol) of sodium cyanide was added thereto, followed by stirring at 65° C. for 2 hours. The reaction mixture was worked up in the same manner as in Example 1-(2) to obtain n-butyl (R)-(-)-4-cyano-3-hydroxybutyrate in a percent yield of 58%.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[C:11](Cl)=[CH:10][C:8]([NH2:9])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1>CN(C)C=O>[Cl:4][C:5]1[C:11]([S:2][CH3:1])=[CH:10][C:8]([NH2:9])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(N)c([N+](=O)[O-])cc1Cl
Yield: 85.7 %

Procedure:
Sodium methanethiolate (4.06 g, 58.0 mmol, Aldrich) was suspended in 80 ml dimethylformamide. 4,5-Dichloro-2-nitroaniline (10.0 g, 48.3 mmol, Aldrich) was added portionwise. Additional sodium methanethiolate (4.38 g, 62.5 mmol) was added over several h until starting material was consumed. The reaction mixture was poured into water (400 ml) and the resulting precipitate was collected by filtration and dried to give 9.05 g (41.4 mmol, 86% yield) of the title compound. 1H NMR (CDCl3) δ8.15 (s, 1H), 6.44 (s, 1H), 2.52 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)[CH:20]=[CH:21][CH:22]=1>>[Cl:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[S:11][C:10]([S:12]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)[CH:18]=3)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:3]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2nsc(Cl)n2)s1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2nsc(Cl)n2)s1
Yield: 68.1 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 5-(5-chloro-1,2,4-thiadiazol-3-yl)thiophene-2-sulfonyl chloride (16.6 mg, 0.055 mmol) and 5-(3-amino-phenyl)tetrazole (8 mg, 0.05 mmol) affording 14.5 mg (68%) of the title compound. MS (ESI+) calcd for C13H8ClN7O2S3 424.959012, found 424.959022.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[C@@H:15]([CH3:30])[CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[CH2:7][OH:8])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:37](Cl)(=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[C@@H:15]([CH3:30])[CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[CH2:7][O:8][C:37](=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41])(=[O:3])[CH3:2]
Reactant: CCCCC(=O)Cl
Reactant: CC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
In 4 ml of methylene chloride was dissolved 208 mg of 17α-acetoxy-11β,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione obtained according to the method as described in Example 6. To this solution was added 0.5 ml of pyridine, and the mixture was ice-cooled. To the mixture was added slowly a solution of 241 mg of valeryl chloride in 2 ml of methylene chloride, and the mixture was stirred for one hour. To this reaction liquid was added 60 ml of ethyl acetate, and the mixture was washed successively with 30 ml of water, 10 ml of a dilute aqueous solution of sodium carbonate, 30 ml of water, 5 ml of dilute hydrochloric acid and twice 30 ml of water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the resultant residue was subjected to preparative thin layer chromatography (silica gel) for purification whereby 186 mg (yield: 87.4%) of the title compound was obtained as colorless needle crystals (recrystallized from ether-hexane). Shown below are physical properties and various analytical data of this compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])c(N)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(N)c(N)c1

Procedure:
Alternate synthesis of a substituted 2-aminobenzimidazole. A mixture of 5-fluoro-2-nitro-phenylamine (1 mmol), an amine (2 mmol) in THF (20 mL) is heated at about 60° C. overnight. After cooling the mixture to room temperature, the reaction mixture is concentrated. The crude material is purified on a silica gel column to yield a 5-amino-2-nitro-phenylamine. The 5-amino-2-nitro-phenylamine (1.0 mmol) is dissolved in an ethyl acetate-methanol mixture (about 1:1, 10 mL) in a round-bottom flask. To this solution Pd—C is added, and the mixture is stirred under a hydrogen atmosphere, while monitoring the reaction with thin-layer chromatography (TLC). After TLC shows completion of the reaction, the solution is filtered on celite and then washed with methanol and concentrated to obtain a 4-amino-benzene-1,2-diamine. The 4-amino-benzene-1,2-diamine (1 mmol) is dissolved in ethanol and CNBr (1.5 mmol) is added. The resulting dark brown solution is heated at 60° C. for 30 minutes. Thereafter, the mixture is cooled to room temperature, and the solvent is evaporated. Then, the mixture is co-evaporated with toluene about two times to obtain a 5-amino-1H-benzoimidazol-2-ylamine as a hydrobromide salt. The reaction scheme below provides an illustration that accompanies this textual description.
Reaction SMILES: F[C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][N:7]2[C:15]1[CH:20]=[C:19]([NH:21][CH:22]=[O:23])[C:18]([F:24])=[CH:17][C:16]=1[F:25].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:32]([NH:39][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][N:7]2[C:15]1[CH:20]=[C:19]([NH:21][CH:22]=[O:23])[C:18]([F:24])=[CH:17][C:16]=1[F:25])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1cn(-c2cc(NC=O)c(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2cc(NC=O)c(F)cc2F)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O

Procedure:
To 30 ml of toluene were added 800 mg of ethyl 5,6,7,8-tetrafluoro-1-(2,4-difluoro-5-formylaminophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate, 0.21 ml of benzylamine, and 240 mg of anhydrous potassium carbonate. The solution was heated at reflux overnight. The reaction solution was allowed to cool down and concentrated in vacua. The residue was combined with chloroform and washed with water. The solution was dried over magnesium sulfate and the solvent was distilled off. Diethyl ether was added to the residue. The solid was collected by filtration and washed with diethyl ether to give 600 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13]Cl.[C-]#N.[K+].[I-].[K+].[CH3:20][N:21](C)C=O>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13][C:20]#[N:21]
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: O
Product: N#CCc1c(Cl)ccc2cc(Cl)cnc12

Procedure:
49 parts of 3,7-dichloro-8-chloromethylquinoline (Example 1), 13 parts of potassium cyanide and 0.1 part of potassium iodide in 300 parts of dimethylformamide were heated at 150° C. for 4 hours. Water was added to the reaction solution and the precipitated product was filtered off with suction and recrystallized from methylglycol. 32 parts of 3,7-dichloro-8-cyanomethylquinoline of melting point 152° C. were obtained. The yield corresponds to 67% of theory.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH:21]([NH2:28])[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH:21]([NH:28][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(CC(N)c2cccnc2)cc1OC
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC(NC(=O)c2ccccc2)c2cccnc2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
9.75 g of benzoyl chloride in 10 ml of chloroform are added, cooling in ice, to 14.9 g of 2-(3,4-dimethoxyphenyl)-1-(3-pyridyl)ethylamine and 12.1 g of triethylamine in 200 ml of chloroform. The mixture is stirred at room temperature for 4 hours, the chloroform is distilled out in vacuo and the residue is washed with toluene and water. 18.5 g of the amide of melting point 156°-158° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:53][C@H:54]([CH2:57][CH2:58][CH2:59][CH3:60])[CH2:55][OH:56].Cl>ClCCl.CN(C=O)C.O>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:53][C@H:54]([CH2:57][CH2:58][CH2:59][CH3:60])[CH2:55][OH:56])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: CCCC[C@@H](N)CO
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Reaction time: 3 h

Procedure:
2 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (Example 3A, 6.28 mmol, 1 equivalent), 2.2 g of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU; 6.9 mmol, 1.1 equivalents) and 3.45 ml of 4-methylmorpholine (31.4 mmol, 5 equivalents) were initially charged in 15 ml of dichloromethane and 10 ml of DMF. 810 mg of (R)-(−)-2-amino-1-hexanol (6.9 mmol, 1.1 equivalents) were added at RT, and the mixture was stirred for 3 h. The mixture was then diluted with dichloromethane and adjusted to pH4 with water and 1 N aqueous hydrochloric acid. The organic phase was separated off and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed twice with water, dried over sodium sulphate, filtered and concentrated. The crude mixture was purified by preparative HPLC (Method 9). This gave 1066 mg (41% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1.N(CCO)CCO>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([OH:11])[CH3:10]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Solvent: C1CCOC1
Solvent: OCCNCCO
Product: C[C@@H](O)c1ccc(Cl)cc1Cl
Temperature: -25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of 2′,4′-dichloroacetophenone (10.9 g, 77.0 mmol) in anhydrous THF (80 mL) at −78° C. under nitrogen was slowly added a solution of (+)-B-chlorodiisopinocampheylborane ((+)-Ipc2BCl, 27.2, 85.0 mmol) in THF (15 mL). After the addition is complete, the reaction mixture was slowly warmed to −25° C. and stirred at this temperature for 2 h. The reaction mixture was then quenched with diethanolamine (17.9 g, 170 mmol), and stirred for 10 min. During this time, a solid formed and it was filtered off. The filtrate was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified flash chromatography (SiO2, 0-20% ethyl acetate in hexanes) to give (R)-1-(2,4-dichlorophenyl)ethanol (12.0 g, 63.3 mmol, 82%).
Reaction SMILES: [O:1]1[CH2:14][CH:2]1[CH2:3][O:4][C:5]1[C:6]([N+:11]([O-:13])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:17][CH2:16]1.C(Cl)Cl>C(O)(C)C>[OH:1][CH:2]([CH2:3][O:4][C:5]1[C:6]([N+:11]([O-:13])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:19][CH2:20]1
Reactant: O=C1NCCN1C1CCNCC1
Reactant: O=[N+]([O-])c1ncccc1OCC1CO1
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C1NCCN1C1CCN(CC(O)COc2cccnc2[N+](=O)[O-])CC1

Procedure:
A mixture of 46.0 g of 3-(2,3-epoxy-propoxy)-2-nitropyridine and 35.0 g of 1-(4-piperidyl)-imidazolidin-2-one in 500 ml of isopropanol is refluxed for 2 hours. Working up analogously to Example 1 using methylene chloride as the extracting agent yields crude 1-{1-[2-hydroxy-3-(2-nitro-3-pyridyloxy)-propyl]-4-piperidyl}-imidazolidin-2-one, which after recrystallisation from isopropanol melts at 154°-158°.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH2:17]O)[C:12]=1[CH3:19]>ClCCl>[Cl:10][C:11]1[C:12]([CH3:19])=[C:13]([CH2:17][F:7])[N:14]=[CH:15][N:16]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1c(Cl)ncnc1CO
Solvent: ClCCl
Product: Cc1c(Cl)ncnc1CF
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
DAST (1.5 mL, 11.35 mmol) was added to dichloromethane (DCM) (64 mL), cooled to −78° C. and treated dropwise with a solution of (6-chloro-5-methyl-4-pyrimidinyl)methanol (Intermediate 50, 1.70 g, 10.72 mmol) in DCM (24 mL) under argon. The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched by adding water (45 ml) and extracted with DCM (×2). The DCM layers were separated, combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (SP4, 40+M) eluting with a gradient of 0-50% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil (1.29 g) m/z (ES+) 161 (M+1), title compound is 42% pure by LCMS. Also contains 4-bromo-6-(fluoromethyl)-5-methylpyrimidine, m/z (ES+) 205, 207 (M+1) (44% by LCMS)
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8](O)=[O:9])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[N:3]1>O1CCCC1>[CH3:1][N:2]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=2)=[N:3]1
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CC(=O)O
Solvent: C1CCOC1
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCO

Procedure:
In analogy to the procedure described for example 9 c], [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-acetic acid was reduced with a 1 M solution of BH3*THF in tetrahydrofuran to give 2-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethanol as colorless crystals.