Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH3:20][C:21]1[S:25][C:24]([C:26](Cl)=[O:27])=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:24]3[S:25][C:21]([CH3:20])=[CH:22][CH:23]=3)=[O:27])[S:11][C:7]=2[C:6]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccccc2)c2sc(N)nc12
Reactant: Cc1ccc(C(=O)Cl)s1
Product: COc1ccc(Oc2ccccc2)c2sc(NC(=O)c3ccc(C)s3)nc12

Procedure:
Using 4-methoxy-7-phenoxy-benzothiazol-2-ylamine and 5-methyl-thiophene-2-carboxylic acid chloride the title compound was obtained crude, which was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2/EtOAc (1:1), to afford the pure title compound as a pale yellow solid (76% yield), MS: m/e=396.0 (M+).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]\[CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:17][N:16]=3)[CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([C:32]2[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=2)[CH:4]=[CH:3]1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][CH2:23]/[CH:22]=[CH:21]/[C:18]1[CH:17]=[N:16][C:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[CH2:8][N:7]2[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:32]3[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=3)=[N:6]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC/C=C\c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC/C=C/c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
48.3 28 mg (0.051 mmol) of tert-butyl [(Z)-3-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)allyl]carbamate are dissolved in 4 ml of dichloromethane, and 79 μl (1.02 mmol) of trifluoroacetic acid are added. The reaction mixture is stirred at room temperature for 15 h and evaporated. The residue is purified by means of preparative HPLC; yield: 11 mg of “A284” trifluoroacetate; HPLC: Rt=2.64 min (method C); LC-MS: 450 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[Si:5]([N:12]1[C@@H:15]([S:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([CH:36]=O)[C:13]1=[O:38])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[Si:5]([N:12]1[CH:15]([S:16][C:17]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]([CH2:36][N:2]([CH3:3])[CH3:1])[C:13]1=[O:38])([C:8]([CH3:10])([CH3:9])[CH3:11])([CH3:7])[CH3:6]
Reactant: CNC
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](C=O)[C@@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C)CC1C(=O)N([Si](C)(C)C(C)(C)C)C1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of dimethylamine (18.5 ml of a 2N solution in methanol, 36.9 mmoles) in methanol (80 ml) was added a solution of hydrochloric acid in methanol (2.5 ml of a 5N solution in methanol) followed by trans 1-(t-butyldimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone (3.0 g, 6.16 mmoles) and by sodium cyanoborohydride (0.27 g, 4.31 mmoles). The mixture was stirred at room temperature for 3.5 h, poured onto ice-hydrochloric acid (pH=2) and made basic with sodium hydroxide (1N NaOH, pH=9). The mixture was extracted with ether and the ether phase was washed with brine, dried and evaporated to give the title compound as a crude oil (3.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:29])[CH2:9]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][C:35]([CH3:37])=O.Cl>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]4[CH2:28][CH2:27][N:26]([CH:35]([CH3:37])[CH3:34])[CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:29])[CH2:9]2)=[C:4]([C:30]([F:33])([F:31])[F:32])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2CCNCC2)c1
Reactant: CC(C)=O
Agent: Cl
Solvent: CCOCC
Product: CC(C)N1CCC(c2cccc(S(=O)(=O)N3CCN(c4ccc(F)cc4C(F)(F)F)C[C@H]3C)c2)CC1

Procedure:
Prepared according to the synthesis of Example 29EZ in Step 4D from (2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-piperidin-4-ylphenyl)sulfonyl]piperazine (81 mg, 0.155 mmol) and acetone (23 μL, 0.31 mmol) as a sticky oil (75 mg, 92%). It was redissolved in Et2O and acidified with 1N HCl in Et2O and triturated with hexanes/Et2O to give the titled compound as a white solid. HRMS: calcd for C26H33F4N3O2S+H+, 528.23023. found (ESI-FTMS, [M+H]1+), 528.22834.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][CH:16]2[O:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][C:26]=1[Cl:38]>>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][CH:16]([OH:18])[CH2:17][NH:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:27][C:26]=2[Cl:38])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOCc1ccc(OCC2CO2)cc1
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Product: CCCCOCCOCc1ccc(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3)cc2Cl)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-n-butyloxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3-(2H)-pyridazinone.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37]>C1COCC1.CCOC(C)=O>[OH:37][CH2:36][C:35]([NH:34][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21])([CH3:39])[CH3:38]
Reactant: CC(C)(N)CO
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)CO)c3)n2)n1
Yield: 63 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.228 g, 0.47 mmol) by treatment with excess 2-amino-2-methyl-1-propanol in THF (10 mL) at 23° C. for 1 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.158 g, 63%) as a white solid. MS (ISP) 541.9 [(M+H)+]; mp 171° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][S:8][CH2:9][CH2:10][Cl:11])[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[ClH:11].[CH3:13][O:5][C:4](=[O:6])[CH:3]([NH2:2])[CH2:7][S:8][CH2:9][CH2:10][Cl:11]
Reactant: CO
Reactant: NC(CSCCCl)C(=O)O
Agent: Cl
Product: COC(=O)C(N)CSCCCl
Reaction time: 12 h
Yield: 100 %

Procedure:
34.2 g of 2-amino-3-(2-chloro-ethylsulfanyl)-propionic acid hydrochloride was dissolved in 300 mL of absolute methanol (treated with Mg) and dry HCl gas (prepared from 250 ml of concentrated sulfuric acid and 200 g of ammonium chloride) was put in the above solution till saturation. And then the mixture was stirred for 12 hour and methanol was removed to obtain 36.3 g white solid. Yield 100%, mp 128-129° C.
Reaction SMILES: [F:1][C:2]1[C:23]([F:24])=[CH:22][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[OH:25][CH2:26]CN1CCNCC1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:23]([F:24])=[CH:22][C:5]2[CH:6]([N:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH2:26][OH:25])[CH2:19][CH2:20]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: CN1CCN(C2Cc3ccccc3Sc3cc(F)c(F)cc32)CC1
Reactant: OCCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: OCCN1CCN(C2Cc3ccccc3Sc3cc(F)c(F)cc32)CC1

Procedure:
A mixture of 7,8-difluoro-10-chloro-10,11-dihydrodibenzo(b,f)thiepine (see Example 15) (6.35 g), 1-(2-hydroxyethyl)-piperazine (6.1 g) and chloroform (10 ml) was refluxed for 7.5 hours under stirring. The chloroform was evaporated under diminished pressure, the residue dissolved in benzene (200 ml) and the solution thoroughly washed with water and shaken with 3 N-HCl (150 ml). The precipitated hydrochloride was filtered, added to the aqueous layer of the filtrate and the resultant suspension made alkaline by addition of ammonium hydroxide. The liberated base was taken up in benzene and the extract yielded 7.1 g (84%) of the desired oily base. This was crystallized from aqueous acetone in the form of the hemihydrate, which in the pure state melts at 101°-102° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14])=O.Cl.[NH2:22][OH:23]>N1C=CC=CC=1.C(OC(=O)C)C>[Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:5](=[N:22]\[OH:23])/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14]
Reactant: NO
Reactant: COc1ccc(C(=O)c2cccc(F)c2F)c(O)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(/C(=N\O)c2cccc(F)c2F)c(O)c1Cl

Procedure:
To a solution of 24 g of 3-chloro-2-hydroxy-4-methoxy-2',3'-difluorobenzophenone in 160 ml pyridine, 22 g of hydroxylamine HCl is added. The mixture is refluxed for 2 hours and the pyridine evaporated in vacuo. The residue is partitioned between ethyl acetate and 5% HCl. The ethyl acetate extract is washed with water, dried over Na2SO4 and evaporated to give a pale yellow solid which consists of two isomers. The solid is melted at 205° C. for approximately 13 minutes. The residue is dissolved in hot ethylacetate and then evaporated to dryness giving E-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone oxime, mp 198°-199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:13]([O-])([O-])=O.[K+].[K+].IC.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Oc1cc(Cl)c2ncccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Cl)c2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a solution of 3.3 g of 8-chloro-6-hydroxyquinoline (Step 1, 3.3 g) in dimethylformamide was added K2CO3 (3.8 g), followed by iodomethane (5.2 g). The mixture was stirred at room temperature overnight. Water was then added and the aqueous mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using 100% CH2Cl2, to give 2.2 g of the desired product as a beige solid; MP=74-75° C.; MS (ES) m/z (relative intensity): 194 (M+H)+ (100).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:14]2[C:13](O)=[N:12][CH:11]=[N:10][C:9]=2[S:8][CH:7]=1.P(Cl)(Cl)([Cl:18])=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:14]2[C:13]([Cl:18])=[N:12][CH:11]=[N:10][C:9]=2[S:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2scc(-c3ccco3)c12
Product: Clc1ncnc2scc(-c3ccco3)c12

Procedure:
5-(2-furyl)-4-hydroxythieno[2,3-d]pyrimidine (180 mg, 0.80 mmol) in phosphorus oxychloride (2.0 ml) was heated to reflux for 2 hours. 5-(2-furyl)-4-chlorothieno[2,3-d]pyrimidine obtained by distilling off the solvent under reduced pressure, without further purification, together with 2-aminoindan (130 mg, 0.98 mmol) and triethylamine (0.90 ml, 6.4 mmol) in dry ethanol (5 ml) was heated to reflux under an argon atmosphere for 2 hours. The residue obtained by distilling off the solvent was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (130 mg, 0.39 mmol) having the following physical properties:
Reaction SMILES: FC1C=CC(CN2C(=O)N(C3SC(C(N)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]([NH2:43])=O)=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:44])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]#[N:43])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:44])=[CH:27][CH:26]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(N)=O
Agent: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(N)=O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C#N
Yield: 68 %

Procedure:
Following the procedure as describe in step A of Example 18, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxamide with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carbonitrile was obtained as a pale yellow solid in 68% yield: mp 136-139° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.31 (m, 2H), 7.18-7.13 (m, 2H), 4.41 (s, 2H), 4.00 (t, J=6.0 Hz, 2H), 3.46 (t, J=6.0 Hz, 2H) 2.37 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.1 (d), 161.4, 161.1, 155.3, 150.3, 132.8 (d), 130.5 (d), 115.9 (d), 114.4, 92.4, 46.6, 42.7, 42.3, 17.3; MS (ES+) m/z 317.91 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=2[N:7]=1.[CH3:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH3:15][N:16]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=2[N:7]=1
Reactant: O=[N+]([O-])c1ccc2oc(CCl)nc2c1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1nc2cc([N+](=O)[O-])ccc2o1

Procedure:
2-Chloromethyl-5-nitrobenzoxazole (2.85 g, 13.4 mmole), N-methyl-4-nitrophenethylamine (J. O. C., [1956], 21, 45) (2.2 g, 12.2 mmole), potassium carbonate (1.85 g, 13.4 mmole) and sodium iodide (2.0 g, 13.4 mmole) were heated under reflux in acetonitrile (50 ml) for 3 days. The solvent was then evaporated, the residue diluted with water, and extracted three times with methylene chloride. The combined organic extracts were washed with water, dried (MgSO4), filtered and evaporated to dryness. The resultant oil was diluted with ether and the supernatant decanted and evaporated to dryness to give an orange solid, which was recrystallised from isopropanol to give the title compound, yield 0.80 g.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[S:25][C:24]([CH:26]=[CH:27][C:28]([O:30]C)=[O:29])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O1CCCC1.CO.O>C(O)(=O)C>[CH3:3][N:4]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[S:25][C:24]([CH:26]=[CH:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(C=CC(=O)OC)s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(C=CC(=O)O)s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
212 mg (5.3 mmol, 10 eq) of sodium hydroxide are added to a solution of 220 mg (0.53 mmol, 1 eq) of methyl 3-(5-{3-[(methyloctanoylamino)methyl]phenyl}thiophen-2-yl)acrylate in 4 ml of 9/1 tetrahydrofuran/methanol. The reaction mixture is stirred for two hours at room temperature. The reaction is stopped by adding 20 ml of water and 3 ml of acetic acid and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (90/10 dichloromethane/methanol). The oil obtained is crystallized from pentane. 155 mg of 3-(5-{3-[(methyloctanoylamino)methyl]phenyl}thiophen-2-yl)acrylic acid are obtained. Yield=73%. m.p.=102-104° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([Sn](CCCC)(CCCC)[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)CCC>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1Br
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1cccnc1

Procedure:
3-(3-Bromo-4-fluorophenyl)-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 3-tri-n-butylstannylpyridine as described in Example 32 to give 3-[4-fluoro-3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine: δH (400 MHz, DMSO) 7.51 (1H, d, J 7), 7.53-7.64 (2H, m), 7.85-7.89 (1H, m), 8.03 (1H, dd, J 7 and 2), 8.12 (1H, dd, J 8 and 2), 8.34 (1H, s), 8.66 (1H, dd, J 5 and 2), 8.90 (1H, t, J 2), 9.38 (1H, d, J 7); m/z (ES+) 359 (M++H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:18]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[NH:20]1[CH2:23][CH2:22][C:21]1=[O:24]>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:18][N:20]3[CH2:23][CH2:22][C:21]3=[O:24])=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: O=C1CCN1
Reactant: ClCc1c(-c2ccccc2)nc2ccc(Cl)cn12
Agent: Cl
Product: O=C1CCN1Cc1c(-c2ccccc2)nc2ccc(Cl)cn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 6-chloro-3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochloride and azetidin-2-one. m/e+ 312 for C17H15ClN3O [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.45 (d, J=1.4 Hz, 1H), 7.72 (d, J=1.4, 3.3 Hz, 2H), 7.62 (d, J=9.5 Hz, 1H), 7.49 (m, 2H), 7.25 (dd, J=2.5, 9.5 Hz, 2H), 4.81 (t, J=4.0 Hz, 2H), 3.20 (t, J=4.0 Hz, 2H), 3.00 (t, J=4.0 Hz, 2H) ppm.
Reaction SMILES: S(Cl)(Cl)=O.N1C2C=CC=CC=2N=N1.[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.[NH2:41][C:42]1[CH:47]=[C:46]([O:48][C:49]2[CH:50]=[C:51]3[C:55](=[CH:56][C:57]=2[O:58][CH2:59][CH2:60][CH2:61][O:62][CH3:63])[N:54]([C:64]([NH:66][CH3:67])=[O:65])[CH:53]=[CH:52]3)[CH:45]=[CH:44][N:43]=1>ClCCl.CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C.O>[CH3:63][O:62][CH2:61][CH2:60][CH2:59][O:58][C:57]1[CH:56]=[C:55]2[C:51]([CH:52]=[CH:53][N:54]2[C:64](=[O:65])[NH:66][CH3:67])=[CH:50][C:49]=1[O:48][C:46]1[CH:45]=[CH:44][N:43]=[C:42]([NH:41][C:29]([C:28]2[CH:27]=[CH:26][C:25]([CH:23]3[CH2:22][N:21]([C:19]([O:18][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:20])[CH2:24]3)=[CH:33][CH:32]=2)=[O:31])[CH:47]=1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)c(OCCCOC)cc21
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(C(=O)O)cc2)C1
Agent: CN(C)c1ccncc1
Agent: c1ccc2[nH]nnc2c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)c4ccc(C5CN(C(=O)OC(C)(C)C)C5)cc4)c3)c(OCCCOC)cc21
Reaction time: 0.08 h
Yield: 43 %

Procedure:
Thionyl chloride (118 μL, 1.62 mmol) was added to a solution of benzotriazole (193 mg, 1.62 mmol) in dichloromethane (5 mL) under nitrogen atmosphere at room temperature, and the mixture was stirred for 5 minutes. 4-(1-(tert-Butoxycarbonyl)azetidin-3-yl)benzoic acid described in Production Example 26-5 (300 mg, 1.08 mmol) was added to the reaction liquid, and the mixture was further stirred for 1 hour. The reaction liquid was filtered through anhydrous sodium sulfate on the glass filter, and the resultant was washed with dichloromethane. A solution of triethylamine (748 μL, 5.40 mmol), 4-dimethylaminopyridine (6.60 mg, 0.054 mmol), and 5-((2-aminopyridin-4-yl)oxy)-6-(3-methoxypropoxy)-N-methyl-1H-indole-1-carboxamide described in Production Example 32-8 (200 mg, 0.54 mmol) in tetrahydrofuran (10 mL) was added to the resultant dichloromethane solution under nitrogen atmosphere at 0° C., and the mixture was stirred for 4 hours and 20 minutes. The reaction liquid was diluted with ethyl acetate and water. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. Tetrahydrofuran and an excessive quantity of methylamine tetrahydrofuran solution were added to the residue, and the mixture was stirred at room temperature. The liquid mixture was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=2:3-0:1) to obtain the title compound (146 mg, 43%).
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]([C:7]12[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:14][CH2:13][C:12](=NN)[CH:11]1[CH2:10][N:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:8]2)=[O:6].C(OCC)(=O)C>O1CCCC1>[CH3:3][O:4][C:5]([C:7]12[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:14][CH:13]=[C:12]([I:1])[CH:11]1[CH2:10][N:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:8]2)=[O:6]
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2c1ccccc1OC
Reactant: II
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1OC
Yield: 48.5 %

Procedure:
106.1 g (0.418 mol) of iodine in 1.1 dm3 of tetrahydrofuran were added dropwise to a solution of 85 g (0.209 mol) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-(2-methoxyphenyl)octahydroisoindole-3a-carboxylate in 2 dm3 of tetrahydrofuran. After addition of 2 dm3 of ethyl acetate, the organic phases were washed with two times 1 dm3 of a saturated aqueous sodium hydrogencarbonate solution, washed with two times 1 dm3 of a saturated aqueous sodium thiosulphate solution, then dried over magnesium sulphate and concentrated under reduced pressure. After purification by chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/05 by volume) mixture, 51 g (48%) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-(2-methoxyphenyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were obtained in the form of a brown oil, the characteristics of which were as follows:
Reaction SMILES: [CH2:1]1[O:11][C:10]2[C:3](=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH:9]=2)[CH:7]=[O:8])[O:2]1.O=[Cr](=O)(O[Cr](=O)([O-])=O)[O-].[NH+:24]1C=CC=CC=1.[NH+]1C=CC=CC=1>>[NH2:12][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:11][C:10]2=[CH:9][C:6]=1[C:7]([NH2:24])=[O:8]
Reactant: c1cc[nH+]cc1
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Product: NC(=O)c1cc2c(cc1N)OCO2

Procedure:
The mixture of 4,5-methylenedioxy-2-nitrobenzaldehyde (12) (1.0 g, 5.1 mmol) and Cornforth reagent (CrO3-pyridine-water) (40 ml) was stirred under reflux for 4 h, and then evaporated. The solid was dissolved in water, and acidified with 10% HCl. The acidified solution was extracted with EtOAc, and dried over MgSO4. After evaporation, the solid was treated as described for the preparation of 10 to afford 16 (0.7 g) as brown powder; MS m/z 180 (M+).