Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1)=[O:4].[CH:13]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][S:23]([CH2:26][CH2:27][NH:28][C:29]([C:31]2[S:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[O:30])(=[O:25])=[O:24])[CH2:18][CH2:17]1)([CH3:15])[CH3:14]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3]([CH2:2][N:22]([CH:19]2[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]2)[S:23]([CH2:26][CH2:27][NH:28][C:29]([C:31]2[S:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[O:30])(=[O:24])=[O:25])=[O:4])=[N:7][CH:8]=1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Product: CC(C)N1CCC(N(CC(=O)Nc2ccc(Cl)cn2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 168 mg (2 equiv.) 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide and 133 mg (0.34 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[O:8]([C:15]1[N:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)C(=O)C>[O:8]([C:15]1[N:20]=[CH:19][C:18]([C:21]2[C:22]3=[N:27][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:23]3[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ncccc1-c1ccc(Oc2ccccc2)nc1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)nc3)C2=N1
Temperature: 60 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
A solution of 2-chloroethanesulfonyl chloride (386 mg) in N,N-dimethylacetoamide (2 mL) was added dropwise to a solution of 6′-phenoxy-3,3′-bipyridin-2-amine (302 mg) in N,N-dimethylacetoamide (2 mL) and additional N,N-dimethylacetoamide (1 mL) was used to complete the addition of above solution. After being stirred at 60° C. for 4 h, the mixture was cooled to room temperature. Water (10 mL) was added dropwise to the reaction mixture and the whole was stirred at room temperature for 0.5 hr. The precipitate was collected by filtration, washed with water (10 mL) and diisopropyl ether (3 mL), and dried in vacuo at 60° C. to give the title compound (323 mg) as an off-white powder.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:33][CH3:34])=[C:10]([CH:32]=1)[C:11]([NH:13][CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=2)[O:16][C:15]1([CH3:31])[CH3:30])=[O:12].C(=O)([O-])[O-].[K+].[K+].C>CS(C)=O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:33][CH3:34])=[C:10]([CH:32]=1)[C:11]([NH:13][CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([S:24]([NH:25][C:3]([NH:2][CH3:1])=[S:4])(=[O:27])=[O:26])[CH:21]=2)[O:16][C:15]1([CH3:31])[CH3:30])=[O:12]
Reactant: COc1ccc(Cl)cc1C(=O)NC1Cc2cc(S(N)(=O)=O)c(OC)cc2OC1(C)C
Reactant: CN=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OC(C)(C)C(NC(=O)c1cc(Cl)ccc1OC)C2
Temperature: 80 °C
Reaction time: 0.42 h

Procedure:
0.26 g (3.5 mmol) of methyl isothiocyanate was added to a suspension of 1.14 g (2.5 mmol) of 3-(5-chloro-2-methoxybenzamido)-2,2-dimethyl-6-sulfamoyl-7-methoxychroman and 1.04 g (7.5 mmol) of finely powdered potassium carbonate in 10 ml of DMSO. After the mixture had been stirred at 80° C. for 25 minutes, it was cooled, introduced into ice/water, clarified with charcoal and acidified to pH 1. The precipitate was filtered off with suction and recrystallized from methanol/DMF. The product had a melting point of 234°-235° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[F:23][C:21]([F:22])([F:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccccc1SC1CCNCC1
Yield: 90 %

Procedure:
To a stirred solution of 2-trifluoromethylbenzenethiol (0.637 g, 0.00358 mole) in DMF (5 mL) was added cesium carbonate (1.396 g, 0.00429 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 0.00358 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed brine solution, dried over sodium sulfate, filtered and concentrated. The resulting residue was washed with hexane to afford 0.81 g (99%) of 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 362.13 (M+1)+, 99%. A solution of 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (0.81 g, 0.00224 mole) in dioxane.HCl (2 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 0.604 g (90%) of 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine hydrochloride which was used in the next step without further purification. LCMS: 262.08 (M+1)+, 95.07%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Cl)[CH:21]=1)=[C:8]([CH3:18])[N:9]2[CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[CH3:2].[CH2:27]([S:29](C1C=CC(S)=CC=1)(=[O:31])=[O:30])[CH3:28]>>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:19][C:20]1[CH:25]=[CH:24][C:23]([S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])=[CH:22][CH:21]=1)=[C:8]([CH3:18])[N:9]2[CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(S)cc1
Reactant: CC(=O)Nc1cccc2c1c(Sc1cccc(Cl)c1)c(C)n2CC(=O)O
Product: CCS(=O)(=O)c1ccc(Sc2c(C)n(CC(=O)O)c3cccc(NC(C)=O)c23)cc1

Procedure:
The title compound was prepared by the method of Example 5 part (iv) using the product from Example 17 part (i) and 4-(ethylsulfonyl)benzenethiol. The product was purified by preparative hplc (eluent MeCN/NH3 (aq)).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.[CH:18]1([CH2:21]Br)[CH2:20][CH2:19]1.[ClH:23]>>[ClH:23].[ClH:23].[CH:18]1([CH2:21][O:17][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[CH:11][C:2]([CH3:1])=[N:3]3)=[CH:8][CH:7]=2)[CH2:20][CH2:19]1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: BrCC1CC1
Agent: Cl
Product: Cc1cc(N2CCCC2)c2ccc(OCC3CC3)cc2n1

Procedure:
In analogy to example 3, from 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 2, and cyclopropylmethyl bromide—with reaction times of 19 h (0° C.) and isolation of the product as hydrochloride, via treatment of the reaction product with HCl-saturated diethyl ether—there was obtained 7-cyclopropylmethoxy-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride as a white solid. ISP mass spectrum, m/e: 283.2 (M+1 calculated for C18H22N2O: 283).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([CH2:11][OH:12])[CH2:5]2.[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:13]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([CH2:11][OH:12])[CH2:5]2)#[N:14]
Reactant: CN(C)C=O
Reactant: OC[C@H]1Cc2ccc(Br)cc2C1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)C[C@@H](CO)C2
Temperature: 175 °C
Yield: 78 %

Procedure:
The (S)-5-bromoindan-2-yl-methanol (600 mg, 2.64 mmol) was mixed with zinc cyanide (480 mg, 4.09 mmol) in DMF (15 mL). To this solution was added palladium tetrakistriphenylphosphine (180 mg, 0.15 mmol). The mixture was heated in a microwave at 175° C. for 20 minutes. Solvents were evaporated and the residue was extracted with ethyl acetate and 0.1N hydrochloric acid. The organic layer was washed with brine and dried over Na2SO4. Solvents were evaporated and the residue was purified through a Biotage flash column chromatography using hexanes and ethyl acetate (2:1 to 1:1 ratio) to give (S)-5-cyanoindan-2-yl-methanol as a colorless oil (357 mg, 78%). Chiral HPLC analysis indicated no racemization.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:19]([NH2:22])[CH:20]=[CH2:21].C(=O)([O-])O.[Na+]>>[CH2:19]([NH:22][C:2]1[N:3]=[C:4]([NH:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:20]=[CH2:21]
Reactant: Cc1csc2c(NN3CCCCC3)nc(Cl)nc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NN2CCCCC2)c2scc(C)c2n1
Yield: 64 %

Procedure:
339 mg (1.2 mmol) of 2-chloro-7-methyl-4-piperidinoaminothieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 233 mg (yield: 64.0%) of the title compound.
Reaction SMILES: [C:1]1([P:7]2(=[O:20])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]2[Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO>[C:1]1([P:7]2(=[O:20])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)N1Cc2ccccc2P1(=O)c1ccccc1
Solvent: CO
Product: O=P1(c2ccccc2)NCc2ccccc21
Temperature: 26 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
The 1-phenyl-2-trimethylsilyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide was dissolved in 50 ml. of methanol and heated at reflux for 4 hours. After stirring for 16 hours at 26° C., the resulting solution was concentrated in vacuo and the residue was crystallized from ethyl acetate to yield 1-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (9.0 g, 33% yield) as a white solid having a melting point of 177°-180° C. and the following analysis:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:9]([Sn](CCCC)(CCCC)C=C)[CH2:10]CC>C1(C)C(C)=CC=CC=1.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>[CH:9]([C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1)=[CH2:10]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: C=Cc1ccc(N)nc1
Yield: 45.3 %

Procedure:
4.13 g 5-bromopyridin-2-yl amine, 7.95 g tributyl(vinyl)tin and 1.38 g tetrakis(triphenylphosphine)palladium were heated in 70 mL xylene at 120° C. for 3 hours under nitrogen atmosphere. The solvent was removed, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate), to give 1.3 g of the title compound as pale yellow crystals.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[NH2:29][C:30]1[C:35]([OH:36])=[C:34]([F:37])[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:32]([CH3:44])[C:31]=1[C:45]#[N:46].[O:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[CH2:52][C:53](O)=O>C(#N)C>[F:37][C:34]1[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:32]([CH3:44])[C:31]([C:45]#[N:46])=[C:30]2[C:35]=1[O:36][C:53]([CH2:52][C:48]1[O:47][CH:51]=[CH:50][CH:49]=1)=[N:29]2
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: O=C(O)Cc1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(-c2ccccc2)c(F)c2oc(Cc3ccco3)nc2c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
With cooling with ice, 1-hydroxybenzotriazole (134 mg, 0.991 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (174 mg, 0.908 mmol) and triethylamine (127 μl, 0.980 mmol) were added to an acetonitrile (8 ml) solution of 4-amino-6-fluoro-5-hydroxy-2-methylbiphenyl-3-carbonitrile (I-41) (200 mg, 0.826 mmol) and 2-furylacetic acid (115 mg, 0.908 mmol), followed by stirring at room temperature for 16 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and the resulting residue was dissolved in xylene (20 ml), then pyridinium p-toluenesulfonate (50 mg) was added, followed by heating under reflux in an oil bath at 160° C. for 1 hour. The reaction liquid was concentrated under reduced pressure, then the residue was dissolved in ethyl acetate, washed with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1, v/v) to obtain the entitled compound (155 mg, 57%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([O:14][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[C:4]([CH:7]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:9]=1)[CH:5]=[O:6]
Reactant: COCCOCCl
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCOc1c(Br)cc(C(C)(C)C)cc1C=O
Temperature: 20 °C
Yield: 100.8 %

Procedure:
A mixture of 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (3.99 g, 15.51 mmol) and anhydrous potassium carbonate (2.36 g, 17.10 mmol) in anhydrous DMF (20.0 mL) was stirred under nitrogen in a water bath (20° C.) to give an orange-yellow suspension. After stirring for 20 min, 2-methoxyethoxymethyl chloride (2.00 mL, 17.66 mmol, technical grade) was added drop wise (30 min) to above suspension while maintaining an internal temperature of 20° C. The reaction mixture was stirred at room temperature for 2.5 h to give a yellow-orange suspension. The reaction mixture was poured into ice-water (150 mL) and stirred at room temperature to give a yellow oily liquid, no solid formation was observed. After 30 min of stirring, the reaction mixture was extracted with dichloromethane (2×100 mL). The organic layer was removed, washed with water (1×50 mL) and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a very pure product as an orange viscous liquid (5.40 g). 1H NMR (400 MHz; CDCl3): δ 1.29 (s, 9H, (CH3)3C—), 3.33 (s, 3H, CH3—O—), 3.53 (M, 2H, —CH2—CH2—O—), 3.98 (M, 2H, —CH2—CH2—O—), 5.25 (s, 2H, —O—CH2—O—), 7.79 (s, 2H, H-4 and H-6), 10.28 (s, 1H, —CHO). The 1H NMR spectrum of the sample was consistent with the suggested structure of the product.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([NH:23]C=O)=[N:17][C:18]=2Cl)C1C=CC=CC=1.C(O)=[O:27]>[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:27])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2
Reactant: O=CNc1nc(Cl)c2ncn(OCCCOCc3ccccc3)c2n1
Reactant: O=CO
Agent: [Pd]
Product: Nc1nc2c(ncn2OCCCO)c(=O)[nH]1
Yield: 33 %

Procedure:
9-(3-Benzyloxyprop-1-oxy)-6-chloro-2-formamidopurine (3.40 g, 9.41 mmol) in 80% formic acid (100 ml) was heated at 100° C. for 1 hour. The reaction mixture was then cooled and stirred with 10% palladium on charcoal (2.0 g) under an atmosphere of hydrogen at 20° C. for 45 minutes. After removal of the catalyst, the solution was evaporated and the residue was treated with water (50 ml) and concentrated aqueous ammonia (4 ml) at 100° C. for 15 minutes. The solution was then cooled and evaporated under reduced pressure. Recrystallisation of the residue from water afforded 9-(3-hydroxyprop-1-oxy)guanine (800 mg, 33%). 1H NMR: δH [(CD3)2SO] 1.80 (2H, quintet, J=6.3, 6.6 Hz, CH2CH2CH2), 3.55 (2H, quartet, J=5.50, 5.8 Hz, CH2OH), 4.32 (2H, t, J=6.6 Hz, CH2ON), 4.57 (1H, t, J=5.5 Hz, D2O exchangeable, OH), 6.57 (2H, br.s, D2O exchangeable, NH2), 7.91 (1H, s, H-8), 10.63 (1H, br.s, D2O exchangeable, H-1).
Reaction SMILES: [Cl:1][CH:2]=[C:3](Cl)[Cl:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[CH:11][C:12]=1[Cl:13].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:14][C:9]1[CH:8]=[C:7]([Cl:6])[C:12]([Cl:13])=[CH:11][C:10]=1[C:3]([Cl:4])=[CH:2][Cl:1]
Reactant: Cc1ccc(Cl)c(Cl)c1
Reactant: ClC=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(Cl)c(Cl)cc1C(Cl)=CCl

Procedure:
A mixture containing 131.5 g (1.0 mole), of trichloroethylene, 80.5 (0.5 mole) of 3,4-dichlorotoluene and 5 g. of aluminum chloride was stirred and heated at reflux for 2 hours. The reaction mixture was then washed with concentrated HCl, then with water until neutral, dried and distilled. 42.7 grams of product was collected, having a boiling point of 97°-102°C at 0.5 mm Hg pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=1[O:14][CH3:13])(=[O:11])=[O:10]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)Cc2ccccc2Cl)c(OC)c1
Reaction time: 0.5 h

Procedure:
At room temperature, 1.24 g of (2-chlorophenyl)methanesulfonyl chloride were initially charged in 30 ml of dichloromethane, and 1.66 ml of 2,4-dimethoxybenzylamine were added dropwise. The reaction mixture was stirred for 30 minutes. Then the mixture was admixed with 50 ml of water and 50 ml of water, and then the aqueous phase was washed once more with 30 ml of ethyl acetate. The combined organic phases were washed with 1 N aqueous hydrochloric acid, dried over MgSO4 and concentrated by rotary evaporation. The residue (1.93 g) was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[NH2:13][C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1O>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][C:15]3[CH:16]=[CH:17][C:18]([Br:20])=[CH:19][C:14]=3[N:13]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: Nc1cc(Br)ccc1O
Product: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1N

Procedure:
Prepared by the method of Example 1a), from 3-amino-4-methoxybenzoic acid (1.84 g, 11.0 mmol) and 2-amino-4-bromophenol (2.0 g, 11.0 mmol) the subtitle compound was obtained (2.0 g, 55%). 1H NMR (CDCl3) δ 7.85(t, 1H), 7.64(dd, 1H), 7.58(d, 1H), 7.41(d, 1H), 6.90(d, 1H), 3.95(s, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:16]2[CH:21]=[C:20]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)[N:19]=[CH:18][N:17]=2)[CH3:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.ClC(OC(Cl)C)=O>C(Cl)Cl>[CH3:34][S:31]([C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:22]([C:20]1[N:19]=[CH:18][N:17]=[C:16]([N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH3:15])[CH:21]=1)[CH2:23][CH2:24]2)(=[O:33])=[O:32]
Reactant: CN(c1cc(N2CCc3cc(S(C)(=O)=O)ccc32)ncn1)C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(c1cc(N2CCc3cc(S(C)(=O)=O)ccc32)ncn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 15 %

Procedure:
7c was taken up in DCM (2 mL). Diisopropylethylamine (0.6 mL, 11 eq) and 1-chloroethyl chloroformate (0.2 mL, 5.7 eq) were added. The reaction mixture was stirred at room temperature for 22 h. The solvent was then evaporated under a stream of nitrogen and the residue was dissolved in methanol and heated at 50° C. for 3 h. The solvent was removed under a stream of nitrogen and the residue was purified by preparative HPLC to give 25 mg (15%) of 7d.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][C:16]=1[O:29][CH2:30][CH2:31][F:32].FC(F)(F)C(O)=O>COCCO>[F:32][CH2:31][CH2:30][O:29][C:16]1[CH:17]=[C:18]([C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])[CH:19]=[CH:20][C:15]=1[NH:14][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1OCCF
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COCCO
Product: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OCCF)ncc1C(F)(F)F
Temperature: 95 °C
Reaction time: 6 h
Yield: 29.3 %

Procedure:
A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.10 g, 0.47 mmol), (4-amino-3-(2-fluoroethoxy)phenyl)(morpholino)methanone (0.13 g, 0.47 mmol), trifluoroacetic acid (0.07 mL, 0.9 mmol) in 2-methoxyethanol (2.5 mL) was stirred at 95° C. for 6 hours. The reaction was the concentrated. The crude product was purified by reverse phase HPLC to give the title compound (61 mg, 29%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[OH:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2](=[O:3])([O:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: OCc1cccs1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(Cl)OC(=O)OCc1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Chloroethyl chloroformate (28.6 g, 0.2 mol) and 2-hydroxymethyl-thiophene (20.6 g, 0.18 mol) were dissolved in chloroform (220 ml) at 0° C. Pyridine (15.8 g, 0.2 mol) was added dropwise during 35 minutes maintaining the temperature below 10° C. After stirring at room temperature for 24 hours the precipitate was filtered off. The organic phase was washed three times with 1 normal hydrochloric acid, once with a saturated sodium hydrogen carbonate solution and finally twice with water. The organic solution was dried with magnesium sulfate and the solvent was removed at reduced pressure. The residue was distilled in vacuo. Yield: 36.5 g. 1H-NMR (DMSO-d6): delta=1.76 (CH3); 5.41 (CH2); 6.53 (CHCH3); 7.04, 7.25; 7.59 ppm (thiophene).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15]Br>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]([CH2:15][C:14]2[CH:13]=[C:12]([F:11])[CH:19]=[C:18]([F:20])[CH:17]=2)[C:2]1=[NH:1]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: Nc1nc2ccccc2[nH]1
Product: N=c1n(Cc2cc(F)cc(F)c2)c2ccccc2n1Cc1cc(F)cc(F)c1

Procedure:
The title compound was prepared from 2-aminobenzimidazole and 3,5-difluorobenzyl bromide by Procedure A. The title product was isolated by filtration and washed with acetonitrile and water to give the title compound as the free base (white solid, mp 144-145° C.). MS(ES+) m/z 386 ([M+1]+, 100).