Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[OH:19])[NH2:15])#[N:11]>CO.O>[OH:19][C:18]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:18]([OH:19])=[C:12]([C:10]#[N:11])[CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:13][C:12]=1[C:10]#[N:11]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: N#Cc1cc(N)ccc1O
Solvent: O
Solvent: CO
Product: N#Cc1cc(Nc2ncc(F)c(Nc3ccc(O)c(C#N)c3)n2)ccc1O
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-cyano-4-hydroxyaniline (241 mg, 1.8 mmol) was added and the mixture was refluxed for 2 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis(4-hydroxy-3-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.96 (d, 1H, J=3.5 Hz), 7.82 (d, 1H, J=3.0 Hz), 7.79 (d, 1H, J=3.0 Hz), 7.71 (dd, 1H, J=3.0, 8.8 Hz), 7.54 (dd, J=3.0, 8.8 Hz), 6.94 (d, 1H, J=8.8 Hz), 6.84 (d, 1H, J=8.8 Hz); LCMS: purity: 97.2%; MS (m/e): 362.98 (M+, 100).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>CS(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([C:13]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:4][O:14]2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ccccc1)c1cccc(Cl)c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1cccc(C2(c3ccccc3)CO2)c1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
A 250 mL-round bottom flask was charged with NaH (60% dispersion in mineral oil) (1.92 g, 0.048 mol), washed with petroleum ether, then treated with dry DMSO (40 mL) under N2. To this reaction mixture was added trimethylsulfoxonium iodide (10.56 g, 0.048 mol) through a solid addition funnel over 15 min. After stirring for 0.5 hr, a solution of 3-chlorobenzophenone (8.66 g, 0.04 mol) in DMSO (15 mL) was added dropwise, and the mixture was heated at 55° C. for 2 hr. The mixture was added to ice-water, extracted with ether (3×100 mL), the organics combined, dried (MgSO4), filtered, and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][C:26](=O)[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.Cl.[NH:32]1[CH2:35][CH2:34][CH2:33]1>C(O)(=O)C>[F:1][C:2]1([F:30])[CH2:3][CH2:4][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][CH:26]([N:32]5[CH2:35][CH2:34][CH2:33]5)[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:6][CH2:7]1
Reactant: C1CNC1
Reactant: O=C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3CCC(N4CCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 133 using 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexyl methyl)-amide, and azetidine hydrochloride in glacial acetic acid. 1H NMR (400 MHz, DMSO-d6): δ 8.76 (t, J=6.0 Hz, 1H), 8.11-8.06 (m, 1H), 7.97-7.94 (m, 1H), 7.76-7.73 (m, 1H), 7.64-7.54 (m, 1H), 4.71 (s, 1H), 3.47-3.16 (m, 1H), 3.07-2.49 (m, 4H), 2.23-2.02 (m, 1H), 2.01-1.95 (m, 6H), 1.90 (s, 6H), 1.64-1.59 (m, 8H. m/z: 478.3 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:8]=[CH:7][C:6]=1[O:24][CH3:25])[CH3:2].Br[C:28]1[CH:29]=[N:30][N:31]([CH2:33][CH2:34][CH3:35])[CH:32]=1>>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:28]3[CH:29]=[N:30][N:31]([CH2:33][CH2:34][CH3:35])[CH:32]=3)[C:13]=2[CH3:23])[CH:8]=[CH:7][C:6]=1[O:24][CH3:25])[CH3:2]
Reactant: CCOC(=O)c1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)ccc1OC
Reactant: CCCn1cc(Br)cn1
Product: CCCn1cc(-n2c(C)c(Sc3ccc(OC)c(C(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 5-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-2-methoxy-benzoic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][CH3:22])[C:11]2[C:6](=[CH:7][C:8]([N+:16]([O-:18])=[O:17])=[C:9]([NH:12]C(=O)C)[CH:10]=2)[N:5]([CH3:19])[C:4]1=[O:20])[CH3:2]>CC(O)C.Cl.O>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[N+:16]([O-:18])=[O:17])[N:5]([CH3:19])[C:4](=[O:20])[C:3]2([CH2:21][CH3:22])[CH2:1][CH3:2]
Reactant: CCC1(CC)C(=O)N(C)c2cc([N+](=O)[O-])c(NC(C)=O)cc21
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCC1(CC)C(=O)N(C)c2cc([N+](=O)[O-])c(N)cc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
A suspension of N-(3,3-diethyl-1-methyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1,38 g) in 2-propanol (5 ml) and hydrochloric acid (6 N; 20 ml) is stirred at 100° C. for 2 h. After cooling the mixture is diluted with water and extracted with CH2Cl2. The organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo to give the desired compound (1.12 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][CH2:33][OH:34].O[C:36]1[CH:45]=[CH:44][C:39]([C:40](OC)=O)=[CH:38][CH:37]=1>C1(C)C=CC=CC=1>[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][CH2:33][O:34][C:36]1[CH:45]=[CH:44][C:39]([CH3:40])=[CH:38][CH:37]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 0.25 h

Procedure:
Di-t-butylazodicarboxylate (9.46 g, 41.08 mmol) is added to a stirred solution of triphenylphosphine (10.77 g, 41.08 mmol), 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol (7.35 g, 36.15 mmol) and methyl 4-hydroxybenzoate (5.0 g, 32.86 mmol) in toluene (120 mL) at 0° C. After stirring for 15 min, the ice-water bath is removed. Stirring is continued for 1 h at RT, 1 h at 40° C., and overnight at RT. The reaction is then concentrated under vacuum, and the residue is crystallized from EtOAc to give 5-methyl-2-phenyl-4-(2-p-tolyloxy-ethyl)-oxazole as a white solid.
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.5 %

Procedure:
To a solution of ethyl(1RS)-1-hydroxy-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (100 mg, 0.23 mmol) in CH2Cl2 (5 ml) was added triethylsilane (32 mg, 0.28 mmol), followed by boron trifluoride etherate (0.13 ml, 1.05 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 10 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to provide the title compound (91 mg, 96%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:33])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]=2[CH:32]=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:33][S:42]([C:39]2[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]=2[CH:32]=1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccc(OC)cc1

Procedure:
6-[(5-Amino-1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=[O:35])[N:5]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[CH:6]2[CH2:12][CH2:13][C:14](NC1C=CC(C(F)(F)F)=CN=1)=[O:15].[CH2:36]([O:38][C:39](=[O:47])[CH2:40][C:41]1[N:42]=[C:43]([NH2:46])[S:44][CH:45]=1)[CH3:37]>>[CH2:36]([O:38][C:39](=[O:47])[CH2:40][C:41]1[N:42]=[C:43]([NH:46][C:14](=[O:15])[CH2:13][CH2:12][CH:6]2[C:7]3[C:3](=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[F:11])[C:4](=[O:35])[N:5]2[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[S:44][CH:45]=1)[CH3:37]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(CCC1c2c(F)ccc(F)c2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(F)(F)F)cn1
Product: CCOC(=O)Cc1csc(NC(=O)CCC2c3c(F)ccc(F)c3C(=O)N2Cc2ccc(F)cc2)n1

Procedure:
The product from Example 18, Part A (100 mg, 0.29 mmol) and (2-amino-4-thiazolyl)acetic acid ethyl ester was converted to the title compound in a manner analogous to the method described in Example 7, Part E without crystallization (70 mg, 47%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH2:31]([N:33]([CH2:44][CH3:45])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[CH3:43])[CH3:32]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=2)=[CH:3][C:2]=1[C:37]1[CH:38]=[CH:39][C:34]([N:33]([CH2:44][CH3:45])[CH2:31][CH3:32])=[C:35]([CH3:43])[CH:36]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(Br)c2)cc1
Reactant: CCN(CC)c1ccc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc(N(CC)CC)c(C)c3)c2)cc1
Yield: 95.5 %

Procedure:
In a manner similar to that of Example 1d, by reacting 1 g (2 mmol) of ethyl 3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylate (obtained in Example 6b) with 630 mg of 4-diethylamino-3-methylphenylboronic acid (3 mmol) in the presence of tetrakis(triphenylphosphine)palladium, 1.1 g of ethyl 4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylate (yield=95%) are obtained in the form of a pale yellow oil.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[CH:4]1[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:8][CH:7]=[C:6](N)[CH:5]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]=[O:27]>>[CH:12]1[C:11]([CH2:10][C:9]2[CH:8]=[CH:7][C:6]([N:1]=[C:2]=[O:3])=[CH:5][CH:4]=2)=[CH:16][CH:15]=[C:14]([N:17]=[C:26]=[O:27])[CH:13]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:2]=[O:3]
Reactant: [N-]=C=O
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Agent: C=O
Solvent: Nc1ccccc1
Product: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1

Procedure:
The instant emulsions are preferably used as binders for materials containing lignocellulose, as already mentioned. Emulsions which have proved to be particularly suitable for this purpose are those in which the isocyanate component (see German Offenlegungsschrift No. 2,711,958) is the phosgenation product for the undistilled bottom fractions. These may be obtained, for example, by the removal of 25 to 90% by weight, preferably 30 to 85% by weight of 2,2'-, 2,4'- and/or 4,4'-diaminodiphenylmethane from an aniline/formaldehyde condensate. The undistilled bottom fraction may also be obtained by the removal of 25 to 90% by weight, preferably 30 to 85% by weight of 2,2'-, 2,4'- and/or 4,4'-diisocyanatodiphenylmethane from the crude phosgenation product of an aniline/formaldehyde condensate. In either case, the isocyanate component should contain 35 to 70% by weight, preferably 45 to 60% by weight of diisocyanatodiphenylmethane. The 2,4'-diisocyanatodiphenylmethane content is from 1 to 8% by weight, preferably from 2 to 5% by weight and the content of 2,2'-diisocyanatodiphenylmethane is from 0 to 2% by weight. In either case, the isocyanate component has a viscosity at 25° C. of 50 to 600 mPas, preferably 200 to 500 mPas, and an isocyanate content from 28 to 32% by weight.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:27])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=3[CH3:26])=[N:13]2)=[O:8])[N:6]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>N1C=CC=CC=1>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([NH:32][CH2:31][CH2:30][O:29][CH3:28])[S:3][CH:4]=3)=[O:8])[CH3:27])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(Br)n3)n2)ccc(C#N)c1Cl
Reactant: COCCN
Solvent: c1ccncc1
Product: COCCNc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)cs1
Temperature: 120 °C
Yield: 38.5 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamide (0.2 g, 0.430 mmol) was added into a microwave vial with dry pyridine as a solvent under nitrogen atmosphere. 2-methoxyethylamine (0.187 ml, 2.152 mmol) was added and the mixture was heated with microwaves at 120° C. Next day a total of 0.187 ml of 2-methoxyethylamine was added and the reaction mixture was heated for additional 3 h. The reaction mixture was evaporated and the crude product dissolved in DCM, washed with Na2CO3, water and brine. The product was purified by Flash-chromatography. Yield 38.5%. 1H-NMR (400 MHz; MeOD): δ 1.25 (d, 3H), 2.50 (s, 3H), 3.35 (s, 3H), 3.40-3.43 (m, 2H), 3.46-3.49 (m, 2H), 4.34 (dd, 1H), 4.41 (dd, 1H), 4.47-4.56 (m, 1H), 6.49 (d, 1H), 7.19 (s, 1H), 7.55 (d, 1H), 7.64 (dd, 1H), 7.73 (d, 1H).
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:35]>>[Cl:35][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]1[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)c1ccc(CCCCCO)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)c1ccc(CCCCCCl)o1
Yield: 60 %

Procedure:
5-(5-Acetyl-2-furanyl)pentanol (9.8 g), 13.1 g of triphenylphosphine and 100 ml of carbon tetrachloride were combined and heated at reflux for 4 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ether and filtered. The filtrate was concentrated and the residue distilled twice to give 2-(5-chloropentyl)-5-acetylfuran, b.p. 100°-102° C. (0.05 mm) in 60% yield.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:9][C:5]1([CH3:8])[N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:3]([CH2:2][O:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:7][O:6]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)COC1(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Reaction time: 17 h
Yield: 84.7 %

Procedure:
A solution of 10.7 g of t-butyl (R)-4-hydroxymethyl-2,2-dimethyl-3-oxazolidinecarboxylate (J. Org. Chem. 52, 1987, 2361-64) in 107 ml of pyridine is treated with 9.7 g of p-toluenesulphonyl chloride. The reaction mixture is stirred for 17 hours, then taken up in ethyl acetate and washed with water. After drying and evaporation the residue is purified over silica gel with hexane/ethyl acetate (3:1). There are obtained 15.1 g of t-butyl (S)-2,2-dimethyl-4-(p-tolylsulfonyloxymethyl)-3-oxazolidinecarboxylate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[N:14](CCCCCCCCC(O)=O)=[N+:15]=[N-:16]>>[N:14]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[N+:15]=[N-:16]
Reactant: O=C(O)CCCCCCCCCBr
Reactant: [N-]=[N+]=NCCCCCCCCC(=O)O
Product: [N-]=[N+]=NCCCCCCCCCC(=O)O
Yield: 91 %

Procedure:
10-bromodecanoic acid (1.125 gr, 4.48 mmol) was reacted as described for product 5a to yield 91% of product 5b. 1H-NMR (200 MHz, CDCl3): 1.2-1.5 (m; 10H), 1.5-1.7 (m; 4H), 2.35 (t; J=7.41 Hz; 2H), 3.24 (t; J=6.81 Hz; 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[H-].[Na+].Br[C:11]1[C:12]2[N:13]([C:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[F:30])=[O:22])=[CH:19][N:20]=2)[N:14]=[C:15]([Cl:17])[CH:16]=1.CO>CN(C=O)C>[Cl:17][C:15]1[CH:16]=[C:11]([NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[C:12]2[N:13]([C:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[F:30])=[O:22])=[CH:19][N:20]=2)[N:14]=1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: Cn1ccc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of 1-methyl-1H-pyrazol-3-amine (37.2 mg, 0.383 mmol) in DMF (0.8 mL) was added 60% NaH (14.10 mg, 0.353 mmol). The mixture was stirred for 10 min. Solid 8A (50 mg, 0.153 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 3 h. Methanol (5 mL) was added and a solid precipitated that was collected by filtration and dried to give 18A (26 mg, 37%) as an off white solid. [M+H]=387. HPLC Peak Rt=2.753 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 254 nm.)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)O)[CH2:5]1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C>[C].[Pd].CO>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCC(C(O)(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)N1CCCC(C(c2ccccc2)c2ccccc2)C1
Temperature: 140 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
To 1-acetyl-3-(diphenylhydroxymethyl)piperidine (500 mg), acetic anhydride (2 ml) was added and the mixture was stirred at 140° C. for 16 hours. After concentration of the reaction solution, 10 ml of methanol and 30 mg of 10% palladium-carbon were added, followed by stirring the mixture under hydrogen atmosphere for 17 hours. Palladium was removed by filtration through Celite and the filtrate was concentrated to obtain 250 mg of 1-acetyl-3-(diphenylmethyl)piperidine. Yield: 52%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].C(N(CC)CC)C.[C:27]([CH:29]([N:31]1[C:35](=[O:36])[CH2:34][N:33]([CH2:37][C:38]#[CH:39])[C:32]1=[O:40])O)#[N:28]>CCOCC>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH:29]([C:27]#[N:28])[N:31]1[C:35](=[O:36])[CH2:34][N:33]([CH2:37][C:38]#[CH:39])[C:32]1=[O:40])=[O:15]
Reactant: C#CCN1CC(=O)N(C(O)C#N)C1=O
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C#CCN1CC(=O)N(C(C#N)OC(=O)C(Nc2ccc(C(F)(F)F)cc2F)C(C)C)C1=O
Reaction time: 18 h

Procedure:
To the acid chloride of 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid (2.5 mmol) in ether is added 1.3 ml of triethylamine followed by the cyano(2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol in 5 ml of ether, from part A above, over about 2 minutes. The reaction mixture is stirred for about 18 hours and then quenched with saturated aqueous sodium bicarbonate. The organic phase is washed with aqueous sodium bicarbonate, water and brine, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a circular chromatograph eluting with 20% ether/hexane to give cyano(2,4-dioxo-1-propargyl-3-imidazolidinyl)methyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate. (A', R is carbonyl, R' is methylene, R1 =R4 is hydrogen, R2 is 2-fluoro-4-trifluoromethylphenyl, R3 is isopropyl, R5 is cyano, R6 is 2-propynyl).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=1.[Cl:11][C:12]1[C:13]([C:18](O)=O)=[N:14][CH:15]=[CH:16][CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[Cl:11][C:12]1[C:13]([C:18]2[N:8]([CH3:9])[C:5]3[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=3[N:10]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: CNc1ccc(I)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(-c2ncccc2Cl)nc2cc(I)ccc21
Temperature: 100 °C
Reaction time: 12 h
Yield: 73.4 %

Procedure:
A mixture of 4-iodo-N1-methyl-benzene-1,2-diamine (850 mg), 3-chloro-pyridin-2-carboxylic acid (590 mg), WSC (790 mg), HOBt (46 mg), and pyridine (10 ml) was stirred at 100° C. for 12 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(3-chloro-pyridin-2-yl)-5-iodo-1-methyl-1H-benzimidazole (930 mg), which is hereinafter referred to as “intermediate compound (M6-21)”.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]2[N:26]=[C:1]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[NH:8][CH:7]=[C:6]4[CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[NH:27][C:22]=2[CH:21]=1
Reactant: CN1CCC(c2c[nH]c3ccc(C=O)cc23)CC1
Reactant: Nc1ccc(Cl)cc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(-c4nc5ccc(Cl)cc5[nH]4)cc23)CC1
Temperature: 155 °C
Reaction time: 24 h
Yield: 65.5 %

Procedure:
A solution of 5-formyl-3-(1-methylpiperidin-4-yl)-1H-indole (0.210 g, 0.90 mmol), and 4-chloro-o-phenylenediamine (0.197 g, 1.38 mmol), in 15 mL of nitrobenzene was heated, with stirring, at 150-160° C. for 24 hours. The solution was allowed to cool to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography (dichloromethane:methanol 10:1.5) to give the title compound (0.215 g, 68%) as an amorphous tan solid. FDMS m/e=365 (M+). EA calculated for C21H21N4Cl.¼ H2O C, 68.28; H, 5.87; N, 15.17. Found: C, 68.32; H, 6.17; N, 14.51.