Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[C:6]1=[O:26].[F:31][C:32]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=1[NH2:34]>>[F:31][C:32]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=1[NH:34][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[C:6]1=[O:26]
Reactant: CC1(C)C(=O)N(c2ccc(Oc3ccccc3)cc2)C(=O)N1Cc1ccccc1Br
Reactant: Nc1ccc(F)cc1F
Product: CC1(C)C(=O)N(c2ccc(Oc3ccccc3)cc2)C(=O)N1Cc1ccccc1Nc1ccc(F)cc1F

Procedure:
To prepare the compound of example 49, the procedure may be according to process “A”. Analogously to the process described in example 1.2, 49.2 and 2,4-difluoroaniline were reacted. 49: Molecular weight 513.18 (C30H25F2N3O3); retention time Rt=2.41 min. [B]; MS (ESI): 514.23 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])OC(C)(C)C)[CH3:22])=[CH:15][CH:14]=4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.Cl.[C:34](OCC)(=O)C>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[CH3:34])[CH3:22])=[CH:15][CH:14]=4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](COc1ccc(-c2nc3ccc(OCC4CC4)cc3o2)nc1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc(-c2nc3ccc(OCC4CC4)cc3o2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [(1S)-2-({6-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]pyridin-3-yl}oxy)-1-methylethyl]carbamate (350 mg) in ethyl acetate (20 mL) was added 4M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in pyridine (15 mL). Acetic anhydride (163 mg) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol), and recrystallized (hexane/ethyl acetate) to give the title compound (201 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[CH3:19][C:20]([CH:23]=O)([CH3:22])[CH3:21].[BH3-]C#N.[Na+].N1C2C=NC=NC=2C=N1>CN1C(=O)N(C)CC1.CO.CCCCCC.C(O)(=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)C=O
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: c1ncc2[nH]ncc2n1
Solvent: CN1CCN(C)C1=O
Solvent: CO
Solvent: CCCCCC
Product: CC(C)(C)CNc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
Analogously to Example 34, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6), 129 mg (1.5 mmol) of pivaldehyde and 180 mg of acetic acid are stirred in 39 ml of DMEU/methanol (1:2) and then reacted with 440 mg (7 mmol) of NaCNBH3. Since, according to HPLC, the reaction is incomplete, 129 mg of pivaldehyde, 180 mg of acetic acid and 440 mg of NaCNBH3 are added a number of times until HPLC indicates that all the pyrazolo-pyrimidine has reacted. Between the individual additions, the reaction mixture is stirred at boiling temperature for 20 hours each time. Analogous working-up and stirring in hexane yield 4-(3-chloro-phenylamino)-3-(2,2-dimethylpropyl-amino)-1H-pyrazolo[3,4-d]pyrmidine; m.p. 229-231° C.; HPLC: tRet(grad20-100/20)=11.6; FAB-MS: (M+H)+=331.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:18][C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]([N+:31]([O-:33])=[O:32])=[C:21](Cl)[N:20]=1.C(O)(=O)C>C1COCC1.O>[Cl:18][C:19]1[N:20]=[C:21]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)[C:22]([N+:31]([O-:33])=[O:32])=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:24]=1
Reactant: Nc1cncnc1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(Nc2cncnc2)nc(Cl)nc1N1CCOCC1
Reaction time: 0.17 h
Yield: 64.9 %

Procedure:
To 0.482 g (5.06 mmol) of 5-aminopyrimidine in THF (10 mL) was added 2.90 mL of NaHMDS (2 M solution in THF) at 0° C., and the mixture was stirred for 10 min. A solution of 0.5924 g (2.12 mmol) of 4-(2,6-dichloro-5-nitro-4-pyrimidinyl)morpholine (U.S. Pat. Appl. Publ. No. 2009/0181963, the disclosure of which is incorporated herein by reference in its entirety) in THF (5 mL) was added, and the resulting mixture was stirred for 15 min. The reaction mixture was neutralized with acetic acid, diluted with water, and extracted with EtOAc. The organic layer was washed with water and aq. NH3, dried, and concentrated. Chromatography on silica, eluting with hexanes/EtOAc (8:2), gave 0.465 g (65% yield) of 2-chloro-6-(4-morpholinyl)-5-nitro-N-(5-pyrimidinyl)-4-pyrimidinamine as a white powder: 1H NMR (DMSO-d6) δ 10.34 (s, 1H), 8.98 (s, 1H), 8.92 (s, 2H), 3.70 (t, J=4.8 Hz, 4H), 3.50 (t, J=4.8 Hz, 4H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH3:11])[C:6]([N+:12]([O-:14])=[O:13])=[C:5](Cl)[N:4]=1.[CH3:16][SH:17]>C(N(CC)CC)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH3:11])[C:6]([N+:12]([O-:14])=[O:13])=[C:5]([S:17][CH3:16])[N:4]=1
Reactant: CS
Reactant: CCNc1nc(SC)nc(Cl)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Product: CCNc1nc(SC)nc(SC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5 g of 2-methylthio-6-chloro-5-nitro-4-ethylamino-pyrimidine are dissolved in 50 ml of absolute alcohol and 2.5 g of triethylamine are then added. Then 1 g of methylmercaptan is passed in at 25° to 30° C over a period of 10 minutes. The mixture is stirred at room temperature for 1/2 hour and subsequently evaporated by rotary evaporation. The residue is suspended in 50 ml of water and filtered off with suction and washed once with water. The product is dried in a water yet vacuum and at room temperature over phosphorous pentoxide for 16 hours to yield 2,6-di-methylthio-5-nitro-4-ethylamino-pyrimidine with a melting point of 149°-150° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[CH2:6][CH:5]([CH3:16])[CH2:4][NH:3]1.Br.N>C(O)(=O)C>[CH3:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)[CH2:6][CH:5]([CH3:16])[CH2:4][NH:3]1
Reactant: COc1ccc(C2CC(C)CNC2C)cc1
Agent: Br
Agent: N
Solvent: CC(=O)O
Product: CC1CNC(C)C(c2ccc(O)cc2)C1
Temperature: 95 °C

Procedure:
A solution of 2.2 g (10 mmol) of 2,5-dimethyl-3-(4-methoxyphenyl)piperidine in 15 ml of a 45% solution of hydrogen bromide in acetic acid was heated at 95° C. for 1 hour. After the addition of another 5 ml of the 45% solution of hydrogen bromide in acetic acid the mixture was heated at 95° C. for a further 90 minutes. After cooling, the reaction mixture was poured on ice, rendered basic with concentrated ammonia and extracted twice with dichloromethane. The organic layer was dried on sodium sulphate, filtered and evaporated under reduced pressure. In this manner 1.7 g (83%) of substantially pure 2,5-dimethyl-3-(4-hydroxyphenyl)piperidine were obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:29]([F:32])([F:31])[F:30])=[N:5][N:6]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[N:23][CH:24]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][CH:17]=[N:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].[Cl:33]C1C(C(F)(F)F)=NN(C2C=CC(S(N)(=O)=O)=NC=2)C=1C1C=CC(C2N=CSC=2)=CC=1>>[ClH:33].[CH2:1]([C:3]1[C:4]([C:29]([F:32])([F:31])[F:30])=[N:5][N:6]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[N:23][CH:24]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][CH:17]=[N:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(-c3cscn3)cc2)cn1
Agent: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(-c2cncs2)cc1
Product: Cl

Procedure:
The title compound was prepared according to the procedure of Example 4 step 4 using 5-[4-ethyl-5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide, instead of 5-{4-chloro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide.
Reaction SMILES: [CH:1]1([C:4]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH:30][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=[CH:20][CH:19]=3)=[C:7]3[N:8]=[C:9]([C:13]([OH:15])=[O:14])[CH:10]=[C:11]([CH3:12])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.N1C=CC=C[CH:39]=1>CO>[CH:1]1([C:4]2[C:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH:30][S:31]([C:34]([F:36])([F:35])[F:37])(=[O:33])=[O:32])=[CH:22][CH:23]=3)=[C:7]3[N:8]=[C:9]([C:13]([O:15][CH3:39])=[O:14])[CH:10]=[C:11]([CH3:12])[N:6]3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C(=O)O)nc2c(Cc3ccc(-c4ccccc4NS(=O)(=O)C(F)(F)F)cc3)c(C3CC3)nn12
Reactant: c1ccncc1
Solvent: CO
Product: COC(=O)c1cc(C)n2nc(C3CC3)c(Cc3ccc(-c4ccccc4NS(=O)(=O)C(F)(F)F)cc3)c2n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of 273 mg 2-cyclopropyl-7-methyl-3-[(-2'-(((trifluoromethyl)sulfonyl)amino)biphen-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxylic acid in 150 mL methanol was added 5 g Amberlyst-15. The mixture was heated to 60° C. for 9 hours (overnight generally preferred). After cooling to room temperature, 5 mL pyridine was added and the mixture was stirred for 30 minutes. The mixture was filtered, was stripped of solvent in vacuo, was stripped from toluene, then was chromatographed on silica gel under medium pressure using 1/1/98 HOAc/MeOH/CH2Cl2 to give 91 mg of the title compound (32% yield) as a yellow solid. Rf 0.58 in 1/3/96 HOAc/MeOH/CH2Cl2, visualized by white light, UV, iodine, and ammonium molybdate/ceric sulfate stain.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.CN(C=O)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Cl:24][C:25]1[N:26]=[CH:27][C:28]([O:31][CH2:2][C:3]2[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=3[CH:4]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)Cn1c(COc2ccc(Cl)nc2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 11 h
Yield: 99 %

Procedure:
6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (1.3 mmol) is dissolved in DMSO (or DMF) (4 ml). To the solution, 2-chloro-5-hydroxypyridine (1.56 mmol) and K2CO3 (1.69 mmol) are added. The mixture is stirred at room temperature under nitrogen atomosphere for 11 h. The reaction mixture is diluted with water and extracted with AcOEt (twice) and Et2O (twice). The combined organic layer is washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to give the product in 99% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([NH:26][C:27](=[O:39])[C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1.O1CCOCC1>CN(C)C=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([NH:26][C:27](=[O:39])[C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1
Reactant: Nc1nc2ccc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc2s1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5ccc(OC(F)(F)F)cc5)cc4s3)c2cc1OC

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)-benzothiazol-6-yl]-4-trifluoromethoxybenzamide was prepared from 4-chloro-6,7-dimethoxyquinazoline (44.9 mg, 0.2 mmol) and N-(2-aminobenzothiazol-6-yl)-4-trifluoromethoxybenzamide (Intermediate 2, 71 mg, 0.2 mmol) according to GP 1. Dimethylformamide was used as a solvent instead of dioxane. After removal of the solvent in vacuo, the residue was subjected to silica gel chromatography applying a dichloromethane-methanol gradient. The product was then further purified by recrystallisation from dichloromethane (3 mL) to obtain a yellow solid (10 mg, 19 μmol, 9%). LC/ESI-MS: m/z=542 [M+H]+; m/z=540 [M−H]−; Rt=3.87 min.
Reaction SMILES: [CH3:1][N:2]([Si](C)(C)C)[C:3](=[O:6])[CH:4]=[CH2:5].[Br:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[CH3:1][N:2]([C:15](=[O:16])[CH2:14][CH2:13][CH2:12][Br:11])[C:3](=[O:6])[CH:4]=[CH2:5]
Reactant: O=C(Cl)CCCBr
Reactant: C=CC(=O)N(C)[Si](C)(C)C
Product: C=CC(=O)N(C)C(=O)CCCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
In a nitrogen glove bag 7.27 g (0.05 mole) of N-methyl-N-trimethylsilylacrylamide was placed in a one-necked flask. The flask was fitted with an additional funnel topped with a drying tube. With the flask contents cooled to ice/water temperatures, 9.28 g (0.05 mole) of 4-bromobutyryl chloride was added dropwise through a dropping funnel to the flask over a period of half an hour. The resulting yellow clear mixture was stirred for an additional two hours. The disappearance of the acyl chloride carbonyl band (1800 cm-1) and the increase in intensity of the product amide band (1670 cm-1) was monitored by IR. The by-product trimethylsilyl chloride was removed in vacuo to give 13 g of product. It was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(C)([O-])C.[K+]>CN(C)C=O.O>[NH:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[O:15][CH2:14][CH2:13]1
Reactant: OCCNc1c(Br)cnc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c3c(cnc2c1)OCCN3
Temperature: 25 °C
Yield: 23.3 %

Procedure:
A mixture of 8.0 g of 3-bromo-N-(2-hydroxyethyl)-4-quinolinamine and 4 g of potassium-tert-butoxide in 220 ml of dimethylformamide was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and diluted with 200 ml of water and the product was extracted with 4 portions of 50 ml of dichloromethane (DCM). The DCM solution was dried over sodium sulfate and concentrated. The oily residue was dissolved in 150 ml of ethanol. To this solution 5 ml of concentrated HCl was added, the HCl salt was separated by filtration and recrystallized from ethanol. This crystalline material was dissolved in 75 ml of water and the solution made alkaline (pH=8) with a sodium bicarbonate solution. The free base was filtered and dried in vacuo to yield 1.3 g of white solid, mp 175°-176° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.O1[CH2:15][CH2:14][NH:13]C1=O.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:15][CH2:14][NH:13][C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCO1
Reactant: Cc1cccc(N=C=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cccc(N2CCNC2=O)c1
Temperature: 195 °C
Yield: 62 %

Procedure:
A mixture of 3-methylphenyl isocyanate (50 mmoles), 2-oxazolidinone (50 mmoles) and anhydrous AlCl3 (40 mg, 0.3 mmole) is heated at 195° C. for 6 hours with stirring. The reaction mixture is dissolved in dichloromethane and the resulting solution is washed with water twice. The dichloromethane solution is dried and evaporated and the residue distilled at reduced pressure. The distillate is recrystallized from hot hexane to give a yield of 62 percent of the desired product, m.p. 137° C.-138° C.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.Br[CH:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23]>C(#N)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])[CH:3]=1
Reactant: CCC(Br)C(C)=O
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Solvent: CC#N
Product: CCC(Oc1cc(N)c(Cl)cc1C(=O)NCCN(CC)CC)C(C)=O
Reaction time: 3 h
Yield: 20.3 %

Procedure:
A solution of the tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (10.5 g, 20 mmoles) (from Prepration No. 3) in acetonitrile (150 ml) was treated with 3-bromo-2-pentanone (3.3 g of 80%, 20 mmoles, contaminated with 15% of 1-bromo-2-pentanone) [obtained according to the procedure of E. T. Borrows, D. O. Holland and J. Kenyon, J. Chem. Soc. 1083, (1946)]. After 3 hours, the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and the solvent evaporated. The semisolid residue was triturated with ether to yield a solid which was recrystallized from ether--petroleum ether to yield 1.5 g of the title compound, mp. 75°-78°. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ 8.26 (s, 1H); 8.14 (bs, 1H); 6.1 (s, 1H); 4.5 (t, 1H); 4.4 (s, 2H); 3.69 (q, 2H); 2.64 (m, 6H); 2.1 (s, 3H); 2.1-1.7 (m, 2H); 1.05 (m, 9H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C@H:17]4[CH2:25][C:24]5[C:19](=[CH:20][C:21](OC)=[CH:22][CH:23]=5)[C@H:18]4[OH:28])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.C1(=O)C2C(=CC=CC=2)CC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C@H:17]4[CH2:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C@H:18]4[OH:28])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)[C@@H](O)[C@@H](N1CCN(c3cccc4c3OCCO4)CC1)C2
Agent: O=C1CCc2ccccc21
Product: O[C@@H]1c2ccccc2C[C@@H]1N1CCN(c2cccc3c2OCCO3)CC1

Procedure:
Prepared in the same manner as the compound of Example 1, but using indan-1-one instead of 6-methoxyindan-1-one in Step 1.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:11][N:10]([CH:12]2[CH2:17][CH2:16][CH:15]([C:18]3[N:22]=[C:21]([C:23]([Cl:26])([Cl:25])[Cl:24])[O:20][N:19]=3)[CH2:14][CH2:13]2)[CH2:9]1)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[Cl:25][C:23]([Cl:24])([Cl:26])[C:21]1[O:20][N:19]=[C:18]([CH:15]2[CH2:16][CH2:17][CH:12]([N:10]3[CH2:11][CH:8]([NH2:7])[CH2:9]3)[CH2:13][CH2:14]2)[N:22]=1.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]
Reactant: CC(C)(C)OC(=O)NC1CN(C2CCC(c3noc(C(Cl)(Cl)Cl)n3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CN(C2CCC(c3noc(C(Cl)(Cl)Cl)n3)CC2)C1
Reaction time: 2 h

Procedure:
{1-[4-(5-Trichloromethyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-azetidin-3-yl}-carbamic acid tert-butyl ester (as prepared in the previous step) was treated with 1:1 ratio of DCM and TFA at room temperature. After 2 hours, the solvent was removed in vacuo and the residue was dried overnight to give the title compound as TFA salt (colorless oil).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)(=O)[CH3:8]>C1COCC1>[CH3:18][N:17]([CH3:19])[C:14]1[CH:15]=[CH:16][C:11]([NH:10][CH2:7][CH3:8])=[CH:12][CH:13]=1
Reactant: CC(=O)Nc1ccc(N(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1ccc(N(C)C)cc1
Temperature: 25 °C

Procedure:
A mixture of LiAlH4 (2.87 g, 71.8 mmol) and N-acetyl-N′,N′-dimethyl-1,4-phenylenediamine (from above) (12.8 g, 17.8 mol) was placed in a soxlet tube and placed in a soxlet extractor with anhydrous THF (200 mL). The mixture extracted with refluxing THF for 50 hrs. The solution was cooled to room temperature and then added wet THF at 0° C. The resultant suspension was filtered and the filtrate was evaporated under high vacuum to obtain a dark oil. The filter cake was extracted with CHCl3 (2×50 mL) by stirring at room temperature. This suspension was filtered and the filtrate dried over NaSO4. The solvent was evaporated to a dark oil which was combined with the other dark oil obtained from the reaction mixture. Distillation afforded the title compound, N,N-dimethyl-N′-ethyl-1,4-phenylenediamine as a yellow oil which darkened upon standing (7.84 g, 67%); b.p. 120-150° C./0.30 mmHg 1H-NMR (d6-acetone): δ(ppm) 1.18 (m, 3H, CH3); 2.80, 2.78 (2×s, 2×3H, 2×NCH3); 3.05 (m, 2H, CH2); 6.60-6.42 (m, 2H, ArH); 6.78-6.60 (m, 2H, ArH).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:11])[CH:9]=2)[NH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1[nH]c2ccc(F)cc2c1Br
Reactant: BrCCCOc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Br)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 134A (465 mg) and 1-(3-bromopropoxy)naphthalene (431 mg) in N,N-dimethylformamide (10 ml) was added cesium carbonate (1059 mg). The reaction was stirred at room temperature overnight and diluted with ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by RPHPLC to provide ethyl 3-bromo-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-D6) δ 8.13 (d, J=7.98 Hz, 1H), 7.85 (d, J=7.67 Hz, 1H), 7.74 (dd, J=9.21, 4.30 Hz, 1H), 7.42-7.58 (m, 3H), 7.37 (t, J=7.98 Hz, 1H), 7.27 (dd, J=8.90, 2.45 Hz, 1H), 7.10-7.20 (m, 1H), 6.85 (d, J=7.36 Hz, 1H), 4.87 (t, J=6.90 Hz, 2H), 4.14 (t, J=5.83 Hz, 2H), 2.21-2.39 (m, 2H).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=3[S:9][C:8]=2[CH:17]=1)=[O:3].[N+:18](=[CH2:20])=[N-:19]>CCOCC>[N+:18](=[CH:20][C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=3[S:9][C:8]=2[CH:17]=1)=[O:3])=[N-:19]
Reactant: Cc1ccc2sc3cc(C(=O)Cl)ccc3c2c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: Cc1ccc2sc3cc(C(=O)C=[N+]=[N-])ccc3c2c1
Reaction time: 8 h

Procedure:
A solution of 2.5 g. of 3-chlorocarbonyl-8-methyldibenzothiophene in 75 ml. of ether was added dropwise to a solution of 0.81 g. of diazomethane in 100 ml. of ether in an ice bath. The solution was stirred overnight, and the ether was removed on the steam bath. The crude product (2.5 g.), 3-diazomethylcarbonyl-8-methyldibenzothiophene, was used directly in the next step.