Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[CH2:12](Br)[CH:13]=[CH2:14]>>[N+:1]([CH:4]=[C:5]1[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:14][CH:13]=[CH2:12])([O-:3])=[O:2]
Reactant: C=CCBr
Reactant: O=[N+]([O-])C=C1NCCCCN1
Product: C=CCN1CCCCNC1=C[N+](=O)[O-]

Procedure:
Method B, reacting hexahydro-2-(nitromethylene)-1H-1,3-diazepine with allyl bromide. Melting point: 82° - 83°.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.Br[CH2:16][CH2:17][CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:24]([O:23][P:19]([CH2:18][CH2:17][CH2:16][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1)(=[O:26])[O:20][CH2:21][CH3:22])[CH3:25]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOP(=O)(CCCBr)OCC
Product: CCOP(=O)(CCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and diethyl (3-bromopropyl)phosphonate according to Method AC (stirred in a sealed vial at r.t. for 16 h, then heating to 80° C. for 4 h before addition of further diethyl (3-bromopropyl)phosphonate, and heating to 90° C. for a further 3 days) and was isolated as a brown gum (64%). LCMS (ES+) 373 (M+H)+, RT 3.73 minutes (Method 1).
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:18])([CH3:17])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])(=O)=O.[CH2:21]([C:23]1[CH-:24][C:25]2[C:30]([CH:31]=1)=[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:28]=[CH:27][CH:26]=2)[CH3:22].[Li+]>CCOCC>[CH3:17][Si:7]([CH3:18])([CH:24]1[C:25]2[C:30](=[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH:31]=[C:23]1[CH2:21][CH3:22])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16]
Reactant: CC1=C(C)C([Si](C)(C)OS(=O)(=O)C(F)(F)F)C(C)=C1C
Reactant: CCc1cc2c(-c3ccccc3)cccc2[cH-]1
Agent: [Li+]
Solvent: CCOCC
Product: CCC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)C1C(C)=C(C)C(C)=C1C
Reaction time: 20 h

Procedure:
To a green solution of dimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silyl trifluoromethanesulfonate (7.50 g, 22.8 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium (2-ethyl-4-phenylindenide) (5.53 g, 24.4 mmol, 1.07 equiv.) in portions to give a hazy yellow solution near room temperature. The reaction was stirred for 20 hours, then evaporated under vacuum, leaving a light yellow semi-solid. The residue was extracted with pentane (3×40 mL) and the extract was filtered to give a yellow solution and pale yellow-white solid. The solution was evaporated under vacuum to yield thick, yellow oil. Yield 9.28 g (102%). 1H NMR(C6D6): δ 7.64 (d, 2H), 7.43 (d, 1H), 7.35 (d, 1H), 7.29 (t, 2H), 7.19 (t, 2H), 6.95 (s, 1H), 3.74, (s, 1H), 3.17 (br s, 1H), 2.46 (m, 1H), 2.32 (m, 1H), 1.95 (s, 3H), 1.89 (s, 3H), 1.82 (s, 6H), 1.05 (t, 3H), −0.22 (s, 6H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][N:6]=1.O>CS(C)=O>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][C:1]#[N:2])=[CH:9][CH:10]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(Cl)nc1
Temperature: 90 °C

Procedure:
25.6 g of sodium cyanide (0.522 mol) are dissolved in 123 g of dimethyl sulfoxide, the mixture is heated to 90° C. and 68.9 g (0.43 mol) of 2-chloro-5-chloromethylpyridine are introduced in portions. During this, the temperature rises to 130° C. The mixture is allowed to cool to room temperature, poured into water and extracted using ether. The solvent is removed and the crude product is distilled at 1.0 mbar (130°-135° C.). M.p.: 80° C. Yield: 41.1 g (63% of theory).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]([OH:30])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:16][C:15]=1[NH:31][C:32](=[O:48])[CH2:33][CH:34]1[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:41][C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Ca+2].O>C1C=CC=CC=1>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]([O:30][C:3](=[O:4])[NH2:5])[CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[CH:16][C:15]=1[NH:31][C:32](=[O:48])[CH2:33][CH:34]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=2[O:41][C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(N)=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
64 μl (0.54 mmol) of trichloroacetyl isocyanate, were added to a solution of 272 mg (0.52 mmol) of N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12) in 6 ml of benzene, and the resulting mixture was stirred for 10 minutes. At the end of this time, a methanolic solution of calcium carbonate was then added, whilst stirring. The reaction mixture was then mixed with water, and the organic phase was separated and dried. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 50 g of silica gel, using a 15:85 by volume mixture of ethyl acetate and methylene chloride as the eluent, to give 135 mg (yield 46%) of the title compound as a foam-like material.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[N:13]=O.[S:15]([O-:18])([OH:17])=[O:16].[Na+].S(=O)(O)[O-].Cl>O>[OH:1][C:2]1[CH:11]=[C:10]([S:15]([OH:18])(=[O:17])=[O:16])[C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[NH2:13]
Reactant: O=Nc1c(O)ccc2ccc(O)cc12
Reactant: O=S([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1c(O)cc(S(=O)(=O)O)c2ccc(O)cc12

Procedure:
In the second reaction stage, the 2,7-dihydroxy-1-nitrosonaphthalene (I) which is generally still moist with water and which reacts in the tautomeric oxime form (Ia), is first suspended, according to Boninger, Chem. Ber. 27, 3050 (1894), in commercially-available 37% aqueous sodium hydrogen sulfite solution and stirred at about 20°-25° C. until it is completely dissolved. The bisulfite addition compound (IIa) thus formed is not isolated, but the brown reaction solution is acidified with hydrochloric acid and heated to about 25°-60° C. 2,7-Dihydroxy-1-aminonaphthalene-4-sulfonic acid (II) is formed by reduction of the nitroso group and aromatization of the cycloaliphatic ring system. The aminonaphtholsulfonic acid (II) is isolated by filtering off the resulting light-gray crystals with suction, washing these on a suction filter first with water and then with methanol and, if desired, drying them. The reaction product thus prepared is used without further purification, if appropriate still moist, for the next reaction stage. The yield of reaction product II is about 90-95% of theory. ##STR6##
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[CH2:18]([N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:30](=[O:32])[CH3:31])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(=O)Cl
Reactant: CCCCCN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCN1CCN(c2cccc3c2C[C@H](NC(C)=O)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-pentylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (170 mg, 0.57 mmol) and triethylamine (86 μL, 0.86 mmol) in methylene chloride (30 mL) was added dropwise acetyl chloride (41 μL, 0.57 mmol) in methylene chloride (10 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The methylene chloride phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue crystallized from diethyl ether/hexane. This gave 120 mg (62% yield) of the title compound as white crystals: mp 119-120° C.; [α]21D +25° (c 0.97, chloroform); EIMS (70 eV) m/z (relative intensity) 343 (49, M+).
Reaction SMILES: [OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][CH:17]([OH:21])[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.C(O[C:35](=[O:37])[CH3:36])(=O)C>N1C=CC=CC=1>[C:2]([O:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][CH:17]([O:21][C:17](=[O:21])[CH3:16])[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([O:30][C:35](=[O:37])[CH3:36])[CH2:3]1)(=[O:1])[CH3:3]
Reactant: CC(C)C(O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Temperature: 0 °C

Procedure:
200 mg of 1α,3β,24trihydroxycholesta-5,7-diene prepared and separated in the same way as in Example 14, (D-1) was reacted with 2ml. of acetic anhydride and 5 ml. of pyridine at 95° C. for 3 hours. The reaction mixture was placed in ice water, and extracted with 40 ml. of diethyl ether. The ethereal phase was washed with dilute hydrochloric acid, then with alkali, and further with water, and dried. The ether was evaporated off to afford 1α,3β,24-triacetoxycholesta-5,7-diene as a slightly yellowish oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.C(OCC)(=O)C>[NH2:16][C:15]1[C:11]2[C:12](=[N:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[C:9]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[CH:10]=2)[O:14][C:31]=1[C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 0.5 g (1.46 mmol) of the product of Step B in 10 mL DMF was added 0.954 g Cs2CO3 and 0.197 mL of 1-bromopinacolone. The reaction was stirred 17 hours at room temperature at which point the reaction mixture was diluted with ethyl acetate and washed with saturated NaCl/NaHCO3 solution (1:1). The residue from the concentrated solution was purified via silica gel flash chromatography eluting with a gradient of 0 to 75% ethyl acetate/hexane to afford the title compound. HPLC-MS: 439.1 (M+1), 441.1 (M+3); Rt=4.53 min.
Reaction SMILES: O[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: Oc1nc(-c2ccccc2)cs1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(-c2ccccc2)cs1

Procedure:
To 80 ml of phosphorus oxychloride were added 7.7 g (43 mmol) of 2-hydroxy-4-phenylthiazole, followed by heating at 100°-105° C. for 2 hours. The solvent was then distilled off from the reaction mixture under reduced pressure. Ice water was added to the residue, followed by extraction with ethyl ether. The ether layer was washed with water. After purification by silica gel column chromatography (solvent: hexane/ethyl acetate=5/1), the title compound was obtained as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[Cl:20][CH2:21][CH:22]1[O:27][CH2:26][CH2:25][NH:24][CH2:23]1>CS(C)=O>[Cl:20][CH2:21][CH:22]1[CH2:23][N:24]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:25][CH2:26][O:27]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: ClCC1CNCCO1
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCl)C3)c(F)c21

Procedure:
A solution of 0.54 g of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.60 g of 2-chloromethylmorpholine in 20 ml of dimethyl sulfoxide is stirred at 120° C. for 8 hours. The reaction mixture is concentrated under reduced pressure and to the residue is added water followed by extracting with chloroform. The organic layer is washed with water, dried over anhydrous magnesium sulfate and then the solvent is distilled off. Further, the obtained crystals are recrystallized from chloroform-methanol to give 7-(2-chloromethylmorpholino)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 212°-215° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1([CH3:22])[O:9][CH:8]([CH2:10][O:11][C:12]2[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:21])[CH2:7][O:6]1>CO>[CH3:4][C:5]1([CH3:22])[O:9][CH:8]([CH2:10][O:11][C:12]2[C:19]([CH3:20])=[CH:18][C:15]([C:16]([NH:2][OH:3])=[NH:17])=[CH:14][C:13]=2[CH3:21])[CH2:7][O:6]1
Reactant: Cc1cc(C#N)cc(C)c1OCC1COC(C)(C)O1
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Yield: 59.7 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy-benzonitrile (5.0 g, 34.0 mmol) in THF (40 mL), rac-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (4.49 g, 34.0 mmol) followed by triphenylphosphine (13.4 g, 50.9 mmol) is added. The mixture is cooled with an ice-bath before DEAD (8.87 g, 50.9 mmol, 23.4 mL of a 40% solution in toluene) is added dropwise. The mixture is stirred at rt for 1 h, the solvent is removed in vacuo and the residue is purified by CC on silica gel eluting with heptane:EA 99:1 to 92:8 to give rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-benzonitrile (7.20 g) as a pale yellow oil; LC-MS: tR=0.99 min, [M+1]+=not detected. b) To a solution of potassium tert.-butylate (6.18 g, 55.1 mmol) in methanol (125 mL), hydroxylamine hydrochloride (5.74 g, 82.7 mmol) is added. To this solution, a solution of rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-benzonitrile (7.20 g, 27.6 mmol) in methanol (40 mL) is added. The mixture is refluxed for 72 h before the solvent is removed in vacuo. The residue is purified by prep. HPLC (XBridge Prep C18, 30×75 mm, 5 μm, 2-95% acetonitrile in water containing 0.5% sat. aq. NH3) to give the title compound (4.85 g) as a pale yellow solid; LC-MS: tR=0.67 min, [M+1]+=295.06; 1H NMR (CDCl3): δ1.43 (s, 3H), 1.48 (s, 3H), 2.29 (s, 6H), 3.76-3.81 (m, 1H), 3.83-3.88 (m, 1H), 3.93-3.99 (m, 1H), 4.17-4.23 (m, 1H), 4.47-4.54 (m, 1H), 5.02 (s br, 1H), 7.28 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])[CH3:2].[OH-].[K+].[O:20]1CCC[CH2:21]1>>[CH2:16]([N:3]([CH2:1][CH3:2])[C:4](=[O:15])[C:5]([CH2:21][OH:20])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])[CH3:17]
Reactant: CCN(CC)C(=O)C(C(=O)O)c1ccccc1
Reactant: C1CCOC1
Agent: [K+]
Agent: [OH-]
Product: CCN(CC)C(=O)C(CO)(C(=O)O)c1ccccc1
Reaction time: 5 h

Procedure:
The phenylmalonic acid diethylamide (2.34 g) obtained in Example 1-b) and paraformamide (390 mg) were suspended in tetrahydrofuran (20 ml), and to this suspension was added potassium hydroxide (catalytic amount) at 60° C. The mixture was stirred for 5 hours and concentrated to remove the solvent. The residue was chromatographed on a column of silica gel with ethyl acetate:hexane=1:1 to give the title compound (2.31 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][CH:15]([CH3:19])[CH2:16][O:17][CH3:18])[N:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([NH:14][CH:15]([CH3:19])[CH2:16][O:17][CH3:18])[N:11]=[CH:10][N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COCC(C)Nc1cc(-c2ccnc(Cl)n2)ncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COCC(C)Nc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ncn1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 2′-chloro-N-(2-methoxy-1-methylethyl) [4,4′-bipyrimidine]-6-amine (i.e., the product of Step C) (100 mg, 0.357 mmol) and 3-chloroaniline (57 mg, 0.45 mmol) in 1,4-dioxane (3.5 mL) under a nitrogen atmosphere was added p-toluenesulfonic acid monohydrate (57 mg, 0.30 mmol). The resulting mixture was stirred at 100° C. for 18 h. The solution was concentrated under reduced pressure to give a yellow solid residue. The residue was then purified on silica gel eluted with 40% ethyl acetate in hexanes, followed by acetone to give 113 mg of title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][C:16](Br)=[C:17](Br)[C:18]=2[CH3:19])[N:11]([CH3:22])[N:10]=1.[ClH:23]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][CH:16]=[C:17]([Cl:23])[C:18]=2[CH3:19])[N:11]([CH3:22])[N:10]=1
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)sc(Br)c1Br
Reactant: Cl
Solvent: CN(C)C=O
Product: Cc1c(Cl)csc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 120 °C
Yield: 55 %

Procedure:
Cuprous chloride (2.9 g) was added to a solution of 3-(2-chloro-6-fluorophenyl)-5-(3-methyl-4,5-dibromothien-2-yl) 1-methyl [1,2,4] triazole in DMF and heated at 120° C. for 12 h under a nitrogen atmosphere. After cooling, HCl (1N) was added and extracted with ether (3×100 mL), washed with brine, dried (Na2SO4), filtered and concentrated to give 1.35 g of crude solid. This was chromatographed on silica gel (Hexane/EtOAc, 3:1, 2:1, 1:1) gave 3-(2-chloro-6-fluorophenyl)-5-(3-methyl-4-chlorothien-2-yl) 1-methyl [1,2,4] triazole as white solid (0.6 g, 55%) MP 117-118° C.; Anal. Calcd. For C14H10BrClFN3S: C, 49.14; H, 2.95; N, 12.28; S, 9.37. Found; C, 48.86; H, 3.03; N, 12.04; S, 9.37.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Cl:9][C:10](Cl)=[CH:11][C:12]1([CH2:17][CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>CN1CCCC1=O.C(Cl)Cl>[Cl:9][CH:10]=[C:11]([C:12]1([CH2:17][CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13]1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-]c1ccccc1
Reactant: CCC1(C=C(Cl)Cl)CCCC1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCC1(C(=CCl)Oc2ccccc2)CCCC1
Temperature: 210 °C
Yield: 87.7 %

Procedure:
140 g (4.2 mol) of sodium phenolate in 500 ml of N-methylpyrrolidone were heated to 200° C. 116 g (0.6 mol) of 1-(2,2-dichlorovinyl)-1-ethyl-cyclopentane were added dropwise so slowly that the reaction temperature did not fall below 195° C. The mixture was then stirred for a further hour at 210° C. After the mixture had cooled, it was diluted with methylene chloride and extracted several times by shaking with 2N sodium hydroxide solution. The organic phase, which had been dried over sodium sulphate, was concentrated in vacuo, and the residue was fractionated. 132 g (88% of theory) of 1-chloro-2-(1-ethylcyclopentyl)-2-phenoxy-ethylene of boiling point 115° to 125° C./0.1 mm Hg were obtained. ##STR17##
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:12]([CH3:13])[CH:11]=[CH:10]2
Reactant: C/C=C/C=O
Reactant: Nc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2cccc(Cl)c2n1
Yield: 40 %

Procedure:
A mixture consisting of 128 g (1.0 mole) of o-chloroaniline, 304 g of conc. hydrochloric acid and 61 g of water was maintained at 90°-95° C., and with sufficient stirring, 70 g (1.0 mole) of crotonaldehyde was added dropwise over the course of 2 hours. After the addition, the mixture was reacted further at 90°-95° C. for 1 hour. The reaction mixture was cooled, and then rendered alkaline by adding a conc. aqueous solution containing 132 g of sodium hydroxide with ice cooling. The alkaline mixture was separated into layers, and the oily layer was distilled at 2-3 mmHg to afford 72 g (0.4 mole) of 8-chloroquinaldine.
Reaction SMILES: C1(C)C=CC(S(CC[O:12][C:13](=[O:48])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]3[S:32]([CH2:34][C:35]3[C:40]([CH3:41])=[C:39]([O:42][CH2:43][CH2:44][CH2:45][O:46][CH3:47])[CH:38]=[CH:37][N:36]=3)=[O:33])(=[O:22])=[O:21])[CH:15]=2)(=O)=O)=CC=1.C([O-])(O)=O.[Na+:54]>CC#N.O>[Na+:54].[CH3:47][O:46][CH2:45][CH2:44][CH2:43][O:42][C:39]1[CH:38]=[CH:37][N:36]=[C:35]([CH2:34][S:32]([C:24]2[N:23]([S:20]([C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[C:13]([O-:48])=[O:12])(=[O:22])=[O:21])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=2)=[O:33])[C:40]=1[CH3:41]
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cccc(C(=O)OCCS(=O)(=O)c3ccc(C)cc3)c2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cccc(C(=O)[O-])c2)c1C
Temperature: 65 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To the solution of the 3-[2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl]benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 48, 1.5 g, 2.0 mmol) in 15 mL of CH3CN was added a solution of NaHCO3 (200 mg, 2.4 mmol, 1.2 eq) in 7 mL of H2O at room temperature, and then the mixture was heated to 65° C. for 2.5 h. Thereafter most of CH3CN was removed, the mixture was extracted with EtOAc, and the aqueous layer was lyophilized overnight. The solid was dissolved in CH2Cl2, and then the mixture was filtered to remove insoluble solids. The filtrate was concentrated to near dryness. The residual oil was dissolved in about 2 mL of CH2Cl2 and EtOAc-ether (1:1) was added to precipitate a white solid. The precipitate was collected by filtration, washed with EtOAc-ether (1:1), and dried under vacuum to give 700 mg (60%) of 3-[2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl]benzoic acid sodium salt (Compound 24) as a white solid.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25](C3N=CN=C(N)C=3OC)[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:38]1[N:43]=[CH:42][N:41]=[C:40]([NH2:44])[C:39]=1[O:45][CH:46]([CH3:48])[CH3:47]>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:23][CH2:24][N:25]([C:38]3[N:43]=[CH:42][N:41]=[C:40]([NH2:44])[C:39]=3[O:45][CH:46]([CH3:48])[CH3:47])[CH2:26][CH2:27]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)Oc1c(N)ncnc1Cl
Reactant: COc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Product: CC(C)Oc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methoxypyrimidin-4-amine using 6-chloro-5-isopropoxypyrimidin-4-amine instead of 6-Chloro-5-methoxy-pyrimidin-4-ylamine. LC-MS: (M+1=531, obsd.=531).