Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:22]([C:21]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:19]([O:18][CH3:17])[CH:20]=1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)cc1OC

Procedure:
Prepared from 2-benzyl-benzo[b]thiophene and 3,4-dimethoxybenzoyl chloride according to the procedure in Example 8. White solid: MS (EI): [M+], 388.
Reaction SMILES: [CH3:1][CH2:2]CCOP(OCCCC)(OCCCC)=O.[C:18]1([C:24]#[C:25][C:26]#[C:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:34][C:35]1[CH:40]=CC(I)=[CH:37][CH:36]=1>>[C:28]1([C:27]#[C:26][C:25]2[CH:24]=[CH:18][C:23]([C:22]#[C:21][C:20]3[CH:19]=[CH:40][C:35]([Br:34])=[CH:36][CH:37]=3)=[CH:2][CH:1]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCCCOP(=O)(OCCCC)OCCCC
Reactant: Brc1ccc(I)cc1
Reactant: C(C#Cc1ccccc1)#Cc1ccccc1
Product: Brc1ccc(C#Cc2ccc(C#Cc3ccccc3)cc2)cc1

Procedure:
In an especially contemplated arm extension strategy depicted in FIG. 4, in which AD represents an adamantane or diamantane group. Phenylacetylene is a starting molecule that is reacted (A1) with TBPA (supra) to yield 1,3,5,7-tetrakis[3′/4′-(phenylethynyl)phenyl]adamantane. Alternatively, phenylacetylene can be converted (B1) to 4-(phenylethynyl)phenylbromide that is subsequently reacted (C1) with trimethylsilylacetylene to form 4-(phenylethynyl)phenylacetylene. TBPA can then be reacted (with phenylethynylphenylacetylene to 1,3,5,7-tetrakis{3′/4′-[4″-(phenylethynyl)phenylethynyl]phenyl}-adarnantane. In a further extension reaction, phenylethynylphenylacetylene is reacted (2) with 1-bromo-4-iodobenzene to form 4-[4′-(phenylethynyl)phenylethynyl]phenylbromide that is further converted (C2) to 4-[4′-(phenylethynyl)phenylethynyl]acetylene. The so formed 4-[4′-(phenylethynyl)phenylethynyl]acetylene may then be reacted (A3) with TBA to yield 1,3,5,7-tetrakis-{3′/4′-[4″-(4′-(phenylethynyl)phenylethynyl)phenylethynyl]phenyl}adamantane.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:13])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc(CO)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CSc1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of 50.0 g (325 mMol) of 4-(methylthio)benzyl alcohol in 350 ml of toluene stirring at room temperature under nitrogen, was added 5 drops of pyridine, and then 28.4 ml (46.4 g, 390 mMol, 1.2 eqs) of thionyl chloride was added dropwise. After 3 hours, ice water was added and the mixture was stirred for 20 minutes. The mixture was transferred to a separatory funnel and shaken thoroughly. The organic layer separated and was dried over sodium sulfate, filtered, and evaporated. Distillation of the residue under reduced pressure gave (4-methylthiophenyl)chloromethane (50.54 g) as a colorless liquid: b.p. 89°-95° C. (1 mm).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ClC(Cl)C(C1C(=O)N(C)C(=O)N(C)C1=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:22]1([CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:19]([CH:8]2[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]2=[O:7])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: CN1C(=O)C(C(=O)C(Cl)Cl)C(=O)N(C)C1=O
Solvent: ClCCl
Product: CN1C(=O)C(C(=O)C(c2ccccc2)c2ccccc2)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (5.00 g, 32.05 mmol), diphenylacetic acid (10.19 g, 48.03 mmol), 4-dimethylaminopyridine (1.95 g, 16.01 mmol) in dry CH2Cl2 (30 ml) was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (7:26 g, 35.22 mmol) added. The reaction mixture was stirred at room temperature overnight and filtered. The solid was washed with CH2Cl2 (150 ml) and the combined solution was washed with 2 N HCl solution (40 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallized from EtOH giving 5-diphenylacetyl-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 9 (6.70 g, 59%).
Reaction SMILES: F[C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]([C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)=[O:37].CN1CCCC1=O>O>[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][C:2]2[C:3]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:40][CH:39]=1)=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2F)CC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 150 °C

Procedure:
To a 350 mL pressure vial is added tert-butyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate (200 mg, 0.711 mmol), Cs2CO3 (417 mg, 1.280 mmol), and (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (305 mg, 1.280 mmol) and N-methylpyrrolidinone (1.3 mL). The reaction was heated in the microwave at 150° C. 1 h. The reaction was added to a flask containing H2O (20 mL) with rapid stirring. The resulting slurry was filtered and the solid filter cake washed with H2O (3×5 mL). The solid was purified by ISCO (40 g SiO2, 0-20% MeOH/CH2Cl2) to give tert-butyl 4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[C:9]=2[CH2:24][OH:25])[CH:5]=[CH:4][N:3]=1.C1(=O)[NH:30]C(=O)C2=CC=CC=C12.[K]>>[NH2:30][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[C:9]=2[CH2:24][OH:25])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(Br)c3)c2cc1OC
Agent: [K]
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(N)c3)c2cc1OC

Procedure:
1-(2-Bromo-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene and potassium phthalimide are treated in the same manner as in Example 6-(2) to give 1-(2-amino-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene which is a hydrolysis product of 1-(2-phthalimide-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene and listed in Table 6.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][N:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24](O)=[O:25])=[CH:16]2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C.Cl.[F:59][CH2:60][CH2:61][NH2:62]>C(Cl)Cl>[F:59][CH2:60][CH2:61][NH:62][C:24]([C:17]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:23]2[N:15]([CH2:14][C:3]2[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])[CH:6]=[CH:5][N:4]=2)[CH:16]=1)=[O:25]
Reactant: Cc1c(OCC(F)(F)F)ccnc1Cn1cc(C(=O)O)c2ncccc21
Reactant: NCCF
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(OCC(F)(F)F)ccnc1Cn1cc(C(=O)NCCF)c2ncccc21
Reaction time: 0.08 h
Yield: 49 %

Procedure:
See FIG. 18(d). 1-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.27 mmol) was taken in DCM (10 mL) to get a clear solution. Triethyl amine (0.190 mL, 1.37 mmol) was added followed by the addition of 1-Propanephosphonic acid cyclic anhydride solution in ethyl acetate (0.326 mL, 0.55 mmol) and stirred the reaction mass for 5 minutes. 2-Fluoroethylamine hydrochloride (54.5 mg, 0.55 mmol) was added and stirred the reaction mass for 3 h. After completion of the reaction, diluted with DCM and then washed with water and brine solution. The organic layer was separated, dried, evaporated and the crude compound was purified by silica gel chromatography using methanol and dichloromethane as eluent. Yield-49%. ES+MS m/z: 411 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.25 (s, 3 H ) 3.67 (q, J=5.21 Hz, 1 H ) 3.76 (q, J=5.21 Hz, 1 H ) 4.50 (t, J=4.99 Hz, 1 H ) 4.66 (t, J=4.90 Hz, 1 H ) 4.90 (q, J=8.85 Hz, 2 H ) 5.68 (s, 2 H ) 7.06 (d, J=5.84 Hz, 1 H ) 7.24 (dd, J=8.38, 4.62 Hz, 1 H ) 7.93 (d, J=7.35 Hz, 1 H ) 8.17 (d, J=5.65 Hz, 1 H ) 8.24 (s, 1 H ) 8.48 (d, J=3.77 Hz, 1 H ) 8.94 (t, J=5.75 Hz, 1 H ).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]([F:21])([F:22])[F:23])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: N#Cc1ccc(O)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (70 mg, 0.44 mmol), 4-hydroxy-3-(trifluoromethyl)benzonitrile (91 mg, 0.49 mmol), K2CO3 (92 mg, 0.66 mmol) in DMF (2 mL) was stirred at 50° C. overnight. Water (4 mL) was added and a precipitate was formed. The solid was filtered-off and it was triturated with MeOH to give the title compound (85 mg) as a brownish solid.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][NH:8][C:9]([C:11]1[C:16]([OH:17])=[C:15]([CH3:18])[N:14]=[C:13]([CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][N:33]=4)=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[N:12]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O.Cl>ClCCl>[CH2:39]([O:38][C:36]([C:35]1[CH:41]=[CH:42][C:32]([C:29]2[CH:30]=[CH:31][C:26]([N:23]3[CH2:24][CH2:25][CH:20]([CH2:19][C:13]4[N:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:43])=[O:5])=[O:10])[C:16]([OH:17])=[C:15]([CH3:18])[N:14]=4)[CH2:21][CH2:22]3)=[CH:27][CH:28]=2)=[N:33][CH:34]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)c1ccc(-c2ccc(N3CCC(Cc4nc(C)c(O)c(C(=O)NCC(=O)OC(C)(C)C)n4)CC3)cc2)nc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2ccc(N3CCC(Cc4nc(C)c(O)c(C(=O)NCC(=O)O)n4)CC3)cc2)nc1
Reaction time: 12 h
Yield: 50.7 %

Procedure:
Ethyl 6-{4-[4-({4-[(2-tert-butoxy-2-oxoethyl)carbamoyl]-5-hydroxy-6-methylpyrimidin-2-yl}methyl)piperidin-1-yl]phenyl}nicotinate (0.043 g, 0.073 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added at room temperature, followed by stirring for 12 hours. Hydrochloric acid (1 M) was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the organic layer was concentrated under reduced pressure. After the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: ethyl acetate/methanol), a fraction corresponding to the Rf value=0.10 (ethyl acetate/methanol=4/1) by thin layer chromatography was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, followed by addition of diisopropyl ether, and subsequently the deposited solid was collected by filtration using diisopropyl ether to afford the title compound (0.020 g, 0.037 mmol) as a pale yellow solid (yield 51%).
Reaction SMILES: O.[OH-].[Li+].O.[CH:5]1([O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:23])[CH:18]=[C:17]3[CH2:24][C:25]2[CH:51]=[CH:50][C:28]([C:29]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]#[C:42][CH2:43][CH2:44][CH2:45][O:46]C(=O)C)(=[O:34])=[O:33])=[O:30])=[CH:27][C:26]=2[O:52][CH3:53])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1>CO.O1CCCC1>[CH:5]1([O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:23])[CH:18]=[C:17]3[CH2:24][C:25]2[CH:51]=[CH:50][C:28]([C:29]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]#[C:42][CH2:43][CH2:44][CH2:45][OH:46])(=[O:33])=[O:34])=[O:30])=[CH:27][C:26]=2[O:52][CH3:53])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C#CCCCOC(C)=O)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C#CCCCO)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
0.37 g of lithium hydroxide monohydrate and 10 ml of water are added to a solution of 1.2 g of N-[4-[5-(cyclopentyloxycarbonylamino)-1-methyl-indol-3-yl-methyl]-3-methoxybenzoyl]-2-(5-acetoxy-pent-1-yn-1-yl)-benzenesulfonamide in 40 ml of methanol/tetrahydrofuran=1/1. The mixture is stirred for 16 hours at room temperature, then the solvents are evaporated off at 15 torr and 40° and 50 ml of methylene chloride are added to the residue. Acidification is effected by adding 50 ml of 1N hydrochloric acid. The organic phase is separated off in a separating funnel. The aqueous phase is extracted twice with 20 ml of methylene chloride each time. The combined organic phases are washed with semi-saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation at 15 torr and 40°. The residue is chromatographed on 45 g of silica gel (Merck, ST 60, 4-63 μm) with 20% hexane in ethyl acetate to yield 1.1 g of the title compound in the form of a white amorphous solid. 1H-NMR (400 MHz, DMSO-d6): 8.90 (s, b, 1H); 8.05 (m, 1H); 7.56 (m, 5H); 7.43 (d, d, 1H); 7.24 (d, 1H); 7.17 (d, d, 1H); 7.15 (d, 1H); 6.96 (s, 1H); 5.08 (m, 1H); 3.97 (s, 2H); 3.92 (s, 3H); 3.68 (s, 3H); 3.47 (t, 2H); 2.47 (t, 2H); 1.92-1.55 (m, 8H); 1.64 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[N:27]1([C:2]2[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: c1ccc2c(c1)CCN2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CN(C)C1CCN(Cc2cc3nc(N4CCc5ccccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 37.2 %

Procedure:
A microwave vessel was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.2 g), indoline (0.12 g), p-toluenesulfonic acid (0.01 g), and DMF (3 mL). The vessel was sealed and heated at 150° C. under microwave irradiation for 4 h. The reaction mixture was cooled to room temperature and the solid precipitate was filtered and purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish the title compound (0.09 g, 38%) as an off-white solid. MS m/e 479 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.36-1.65 (m, 2H) 1.85 (d, J=11.30 Hz, 2H) 2.06 (t, J=10.74 Hz, 2H) 2.44 (br. s., 6H) 2.97 (d, J=11.30 Hz, 2H) 3.12 (t, J=8.48 Hz, 3H) 3.67-3.93 (m, 10H) 4.17 (t, J=8.67 Hz, 2H) 6.84 (t, J=7.35 Hz, 1H) 7.03-7.29 (m, 3H) 8.31 (d, J=7.91 Hz, 1H).
Reaction SMILES: [C:1]1(C)[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH:12][CH2:13][C@@H:14]1[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.[CH2:27](N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[S:7]([O:12][CH2:13][C@@H:14]1[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)([C:2]1[CH:1]=[CH:6][C:5]([CH3:27])=[CH:4][CH:3]=1)(=[O:8])=[O:9]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CO)C1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reaction time: 24 h
Yield: 88.4 %

Procedure:
Toluene sulphonyl chloride (0.473, 2.48 mmol) was added to a solution of (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (0.360, 1.65 mmol), triethylamine (0.45 mL, 3.30 mmol) and DMAP (cat.) in dichloromethane (10 mL). The reaction mixture was stirred for 24 h then diluted with dichloromethane (20 mL) and washed sequentially with water (20 mL) and 0.2M HCl (20 mL). The organic phase was dried (Na2SO4) and solvent was removed in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1/5), to give the title compound as a colourless solid (0.542 g, 88%).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][O:14][C:15]1[C:22]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:21][C:18]([CH:19]=O)=[C:17]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:16]=1>>[CH3:13][O:14][C:15]1[C:22]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:21][C:18](/[CH:19]=[CH:2]/[C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=2)=[O:3])=[C:17]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH:16]=1
Reactant: COc1cc(OCCCN2CCOCC2)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(N)=O)cc1
Product: COc1cc(OCCCN2CCOCC2)c(/C=C/C(=O)c2ccc(C(N)=O)cc2)cc1-c1cccs1

Procedure:
The title compound was prepared by condensing 4-Acetyl-benzamide (Ex-92A) and 4-methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde (Ex-66A) in a similar manner as described in Ex-92. Orange solid, mp 81–83° C. 1H-NMR (CDCl3) δ 8.08 (m, 3H), 7.94 (d, 2H), 7.86 (s, 1H), 7.56 (d, 1H), 7.41 (d, 1H), 7.32 (d, 1H), 7.10 (m, 1H), 6.55 (s, 1H), 4.19 (t, 2H), 3.99 (s, 3H), 3.72 (t, 4H), 2.59 (t, 2H), 2.12 (t, 4H), 1.98 (quintet, 2H). MS m/z=506 ([M]+, 34%), 100 (100%). 28%. Anal. calculated for C28H30N2O5S.2/5H2O: C, 65.45; H, 6.04; S, 6.24; found C, 65.30; H, 6.16; S, 6.17.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][CH2:6][N:7]([S:31]([CH3:34])(=[O:33])=[O:32])[C:8]2[C:9]([CH:28]3[CH2:30][CH2:29]3)=[CH:10][C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:12]=3[C:24]([NH:26][CH3:27])=[O:25])[CH2:2]1.[CH2:35]=O.[BH4-].[Na+].O>CO>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:13]2[C:12]([C:24]([NH:26][CH3:27])=[O:25])=[C:11]3[C:15]([CH:16]=[C:8]([N:7]([CH2:6][CH2:5][CH:3]4[CH2:4][N:1]([CH3:35])[CH2:2]4)[S:31]([CH3:34])(=[O:33])=[O:32])[C:9]([CH:28]4[CH2:29][CH2:30]4)=[CH:10]3)=[N:14]2)=[CH:22][CH:21]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CNC3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CN(C)C3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Yield: 124 %

Procedure:
To a solution of Compound (6) (27 mg, 0.05 mmol) in MeOH (2 mL) was added, simultaneously, paraformaldehyde (30 mg) and sodium borohydride (30 mg). After 16 h at ambient temperature water (25 ml) was added and the aqueous layer was extracted into EtOAc (3×30 mL). The combined organics were washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo to give a colourless oil (32 mg). The crude material was purified by reverse phase preparative LCMS: Acetonitrile/water (0.1% formic acid) to give Compound (7) (7.70 mg, 30%). ESI-MS m/z calculated for [M+H]+: 516.2. found: 516.1. 1H NMR (400 MHz, CD3CN, formate salt) δ 8.30 (s, 1H), 7.79 (s, 1H), 7.62-7.49 (m, 4H), 7.35 (s, 1H), 7.22 (br s, 1H), 3.84-3.70 (m, 2H), 3.70-3.56 (m, 2H), 3.38 (dd, J=16.0, 7.5 Hz, 2H), 3.07 (s, 3H), 2.89 (d, J=4.8 Hz, 3H), 2.75 (dt, J=15.4, 7.8 Hz, 1H), 2.51 (s, 3H), 2.35 (ddd, J=13.6, 8.1, 5.6 Hz, 1H), 1.87 (ddd, J=17.6, 11.0, 5.2 Hz, 2H), 1.11-0.98 (m, 3H), 0.65-0.57 (m, 1H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.CN(C)C=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([CH3:26])=[C:24]([C:27]([OH:29])=[O:28])[CH:23]=[N:22]2)=[CH:17][CH:16]=1>O>[CH3:1][O:28][C:27]([C:24]1[CH:23]=[N:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=2)[C:25]=1[CH3:26])=[O:29]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cnn(-c2ccc(Cl)cc2)c1C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
Potassium carbonate (8.76 g) and methyl iodide (3.15 ml) were added to a N,N-dimethylformamide solution (42 ml) of 1-(4-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (10.0 g) in Reference Example 3 at room temperature and stirred for five hours. Potassium carbonate (4.08 g) and methyl iodide (2.1 ml) were subsequently added and the mixture was stirred further for three hours at room temperature. After completion of the reaction, water (200 ml) was added and the precipitated solid was collected by filtration to give 1-(4-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester (10.5 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.CN(CCN(C)C)C.C([Li])CCC.[CH2:25]([O:27][C:28](=[O:36])[C:29](=[CH:32]OCC)[C:30]#[N:31])[CH3:26]>C1(C)C=CC=CC=1.O>[CH2:25]([O:27][C:28](=[O:36])/[C:29](/[C:30]#[N:31])=[CH:32]/[C:10]1[C:4]2[O:3][C:2]([F:1])([F:11])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)[CH3:26]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: FC1(F)Oc2ccccc2O1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C#N)=C/c1cccc2c1OC(F)(F)O2

Procedure:
40.0 g (253 mmol) of 2,2-difluoro-1,3-benzodioxole in 29.5 g (254 mmol) of TMEDA and 35 ml of toluene are metallated analogously to Example 2c) at from -15° to -10° C. with 106.2 g (307 mmol) of n-butyllithium solution (18.5% in toluene). 52.1 g (308 mmol) of ethoxymethylenecyanoacetic acid ethyl ester in 115 ml of toluene are added to the reaction mixture at from -15° to -10° C. over a period of 2 hours. The resulting suspension is poured, after 20 minutes at +10° C., into 350 ml of water, the aqueous phase is separated off and the organic phase is concentrated by evaporation in a vacuum rotary evaporator to yield the desired product.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]2)[CH:15]=[N:16][CH:17]=1)[CH3:10]>>[Br:1][C:17]1[N:16]=[CH:15][C:14]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:20][CH2:19]2)=[CH:13][C:12]=1[O:11][CH2:9][CH3:10]
Reactant: CCOc1cncc(N2CCCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: O=C1CCC(=O)N1Br
Product: CCOc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cnc1Br
Reaction time: 0.03 h

Procedure:
N-Bromosuccinimide (2.7 g, 15.2 mmol) was added to 1-(5-Ethoxy-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (4.5 g, 14.0 mmol) at room temperature. The mixture was stirred for 2 min. The mixture was washed with saturated sodium sulfite (100 ml) was. Chromatography on silica gel with a mixture of petroleum:ethyl acetate (1:1) gave the title compound as an oil. Yield 3.3 g, 58%.