Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C@H:2]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][OH:4])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N[C@@H](CO)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
To a solution of 12.18 g (0.0756 mol) of L-serine, t-butyl ester, 26.52 ml of triethylamine in 160 ml of CH2Cl2 (cooled in an ice bath) was added, in small portions, 16.1 g (0.0771 mol) of 4-methoxybenzene-sulfonyl chloride. The mixture was stirred at 0° C. for 0.5 hours and at room temperature overnight. The mixture was washed with H2O, 2N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 25.34 g of solid which was triturated with hexane. The solid was recrystallized from 120 ml of toluene to give 12.18 g (48.7%) of product as a white solid. The filtrate was concentrated and the residue chromatographed on silica gel with hexane-ethyl acetate (7:3) as eluent to give 5.71 g (22.8%) of white solid. m.p. 70-75° C. Anal. for C14H21NO6S: Calc'd: C, 50.7; H, 6.4; N, 4.2; Found: C, 50.4; H, 6.3; N, 4.4.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7])[CH3:2].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])[CH3:2]
Reactant: CCN(CC)CCCN
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)NCCCN(CC)CC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
13.0 g of N,N-diethyl-1,3-diaminopropane were added to 70 ml of diethyl oxalate with stirring at room temperature over a period of 20 minutes. After stirring at room temperature for 2 hours, excess diethyl oxalate was distilled off under reduced pressure to obtain 21.7 g of N,N-diethyl-N'-ethoxalyl-1,3-diaminopropane as an oily product. 6.90 g of this oily product and 3.99 g of 3-(2-methoxyethoxy)propylamine were dissolved in 30 ml of methanol and the solution was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure to obtain 9.51 g of Compound B-1 as an oily product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH:9]([CH3:20])[C:10]([N:12]1[C@H:16]([C:17]([OH:19])=[O:18])[CH2:15][S:14][CH2:13]1)=[O:11].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([O-:28])=[S:27])=[CH:24][C:23]=1[S:31](=[O:34])(=[O:33])[NH2:32].[K+].[CH:36]1([NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O>[CH:43]1([NH:42][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([S:27][CH2:8][C@@H:9]([CH3:20])[C:10]([N:12]2[C@H:16]([C:17]([OH:19])=[O:18])[CH2:15][S:14][CH2:13]2)=[O:11])=[O:28])=[CH:24][C:23]=1[S:31](=[O:34])(=[O:33])[NH2:32]
Reactant: CC(CBr)C(=O)N1CSC[C@H]1C(=O)O
Reactant: NS(=O)(=O)c1cc(C([O-])=S)ccc1Cl
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[C@H](CSC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)C(=O)N1CSC[C@H]1C(=O)O

Procedure:
A solution of 1.4 g of potassium carbonate in 30 ml of water is added to 2.8 g of 3-(3-bromo-2-methylpropionyl)-4(R)-thiazolidinecarboxylic acid whereupon 3 g of potassium 4-chloro-3-sulfamoyl-thiobenzoate is added slowly under ice-cooling and stirring, and the resulting mixture is stirred at room temperature for 4 hours. The reaction mixture is then treated in an analogous manner of Example 1, and the oily residue thus obtained is converted in a conventional manner into the dicyclohexylamine salt. Thus is obtained dicyclohexylamine salt of 3-[3-(4-chloro-3-sulfamoylbenzoylthio)-2(S)-methylpropionyl]-4(R)-thiazolidinecarboxylic acid as white crystalline powder, melting at 173°-176° C. (recrystallized twice from isopropanol).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:19]([C:22](=[O:35])[CH2:23][NH:24][C:25]([CH3:34])([CH3:33])[CH2:26][CH2:27][N:28]2[CH:32]=[N:31][N:30]=[CH:29]2)=[CH:18][C:13]=1[C:14](OC)=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[BH4-].[Na+].CC(C)=O>C(O)C.O1CCCC1.C(O)(=O)C>[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:19]([CH:22]([OH:35])[CH2:23][NH:24][C:25]([CH3:34])([CH3:33])[CH2:26][CH2:27][N:28]2[CH:29]=[N:30][N:31]=[CH:32]2)=[CH:18][C:13]=1[CH2:14][OH:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(C(=O)CNC(C)(C)CCn2cnnc2)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CCO
Product: CC(C)(CCn1cnnc1)NCC(O)c1ccc(OCc2ccccc2)c(CO)c1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
5 g of calcium chloride are dissolved in 50 mL ethanol. Then 10 g of methyl 2-benzyloxy-5-[2-(1,1-dimethyl-3-[1,2,4]triazol-4-yl-propylamino)-acetyl]-benzoate in 100 mL tetrahydrofuran are added and the mixture is cooled to 5° C. It is combined batchwise with 3.5 g of sodium borohydride and stirred overnight while heating to ambient temperature. 15 mL acetone are added to the reaction mixture and it is stirred for 30 minutes. Glacial acetic acid is added, the solvents are distilled off, 100 mL water are added to the residue and it is adjusted to pH 2 with conc. hydrochloric acid. It is washed once with ethyl acetate, then made basic with ammonia, diluted with 100 mL water and extracted twice with in each case 200 mL ethyl acetate. After the organic phase has been dried it is evaporated down and the residue is dissolved in acetonitrile. The mixture is acidified with glacial acetic acid and seed crystals are added. The product precipitated is suction filtered and recrystallised from acetonitrile. Yield: 6.5 g (43%, acetate); m.p.=139-141° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.[CH2:13]([CH:15]([NH2:18])[CH2:16][CH3:17])[CH3:14]>C1COCC1>[Cl:12][C:4]1[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CCC(N)CC
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: C1CCOC1
Product: CCC(CC)Nc1nc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 4 h
Yield: 35.9 %

Procedure:
A mixture of 2-methyl-5-nitro-4,6-dichloro-pyrimidine (208 mg, 1.00 mmol) and 1-ethyl-propyl-amine (87 mg, 1.03 mmol) in 2 ml of dry THF was stirred at −78° C. for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a green oil. The oil was purified through silica gel column chromatography using chloroform to 1:1 hexane/chloroform as eluent to give the title compound (93 mg, 35%). 1H NMR (CDCl3) δ 7.50 (brs, 1H), 4.29 (m, 1H), 2.51 (s, 3H), 1.4–1.8 (m, 4H), 0.92 (t, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]2[N:35]=[C:36]([CH:38]=O)[N:37]=[C:30]2[N:29]=1.N(C)C.Cl>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[C:17]([CH2:38][C:36]3[N:37]=[C:30]4[N:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]4[N:35]=3)=[C:16]([OH:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(OC(C)C)c(Cl)c4)(C4CCCC4)OC3=O)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (0.3 g, 0.79 mmol) and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.17 g, 0.95 mmol, described in Step 3 of example B(75)) were dissolved in 3:1 MeOH/CH2Cl2 (4 mL). To this suspension, Me2NH.BH3 (0.07 g, 1.19 mmol) was added as a solid from top. After stirring 1 h at room temperature, the reaction mixture became clear and it was stirred for an additional 5 hours. After this time, 1 M HCl (1 mL) was added and the reaction stirred for 30 minutes at room temperature, the solvent was the evaporated to half the volumen and extracted 3 times with 10% MeOH/CH2Cl2 (10 mL). The organic phase was dried over MgSO4 and evaporated. The residue purified by flash column chromatography (80% EtOAc in hexanes) to eliminate unreacted pyrone and reduced 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde, then 3% MeOH/CH2Cl2 to give the product (0.1 g, 24%) as a white solid. 1H NMR (DMSO-d6): δ 1.14 (d, J=6.3, 6H), 1.4-1.53 (m, 8H), 1.7-1.75 (m, 2H), 1.95-1.98 (m, 1H), 2.35-2.44 (m, 8H), 3.19 (s, 2H), 3.57 (d, J=16 Hz, 1H), 3.69 (d, J=16 Hz, 1H), 4.41-4.47 (m, 1H), 6.91-6.93 (s, 1H), 7-7.07 (m, 2H), 7.10 (d, J=2.0, 1H), 10.7 (brs, 1H). Anal. Calcd. For C29H35N4O4: C, 64.61; H, 6.54; N, 10.39. Found: C, 64.30; H, 6.81; N, 10.35. ESIMS (MH+): 540
Reaction SMILES: O[C:2]([C:5]1[N:6]=[C:7]([CH2:39][CH2:40][CH3:41])[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:9]=1[C:10]([O:12][CH2:13][C:14]1[O:15][C:16](=[O:20])[O:17][C:18]=1[CH3:19])=[O:11])([CH3:4])[CH3:3].CN(C)C(=O)C.S(=O)(=O)(O)O.[OH-].[Na+]>C(Cl)Cl.O>[C:2]([C:5]1[N:6]=[C:7]([CH2:39][CH2:40][CH3:41])[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:9]=1[C:10]([O:12][CH2:13][C:14]1[O:15][C:16](=[O:20])[O:17][C:18]=1[CH3:19])=[O:11])([CH3:4])=[CH2:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=C(C)c1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1C(=O)OCc1oc(=O)oc1C
Temperature: 40 °C
Yield: 116.7 %

Procedure:
(5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate [olmesartan medoxomil] (20.0 g) was added into anhydrous N,N-dimethylacetamide (80 ml) under a nitrogen stream, and after dissolution was confirmed, concentrated sulfuric acid (3.0 ml) was poured in and the mixture was reacted at about 100° C. for 2.5 hours. Upon completion of the reaction, the reaction mixture was cooled to about 40° C. and poured into cold water (80 ml). After methylene chloride (80 ml) was poured in, the pH of the reaction mixture was adjusted to 4.2 with 25% sodium hydroxide. The organic layer was separated, washed with brine (80 ml) and concentrated under reduced pressure to obtain 22.58 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-isopropenyl-2-propyl-1-[[2′-[1H-tetrazol-5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate [crude olmesartan medoxomil dehydrate] as a foam.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2)([O-:5])=[O:4].[CH3:15]I.[NH4+].[Cl-]>CN(C=O)C.O.CCOC(C)=O>[CH3:15][N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCc2cc([N+](=O)[O-])ccc21
Temperature: 23 °C
Reaction time: 15 h

Procedure:
25 ml of anhydrous DMF is introduced into a 150 ml three-necked flask, under an inert atmosphere, followed by 0.84 g (21 mmol) of 60% NaH. The reaction mixture is cooled down using an ice bath before the dropwise addition of a solution of 3.28 g (20 mmol) of 5-nitroindoline in 5 ml of anhydrous DMF. At the end of the addition, agitation is maintained for 1 hour at 23° C., before introducing dropwise a solution of 1.31 ml (21 mmol) of MeI in 5 ml of anhydrous DMF. Agitation is continued for 15 hours at 23° C. The reaction is finally neutralized, at 0° C., with 20 ml of a saturated solution of NH4Cl. The reaction mixture is then diluted with 20 ml of water and 50 ml of AcOEt. After decanting, the organic phase is washed successively with 20 ml of water then 20 ml of salt water, dried over magnesium sulphate, filtered and concentrated under vacuum. A dark yellow powder is obtained.
Reaction SMILES: O(CC(O)=O)C1C=CC=CC=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][C:24](O)=O.[CH2:27]([NH:30][CH:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[O:41][CH3:42])[CH2:32]1)[CH2:28][CH3:29]>>[CH3:42][O:41][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:38]=1[CH2:39][CH2:40][CH:31]([N:30]([CH2:24][CH2:23][O:22][C:13]1[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=1)[CH2:27][CH2:28][CH3:29])[CH2:32]2
Reactant: O=C(O)COc1ccc2ccccc2c1
Reactant: CCCNC1CCc2c(cccc2OC)C1
Agent: O=C(O)COc1ccccc1
Product: CCCN(CCOc1ccc2ccccc2c1)C1CCc2c(cccc2OC)C1

Procedure:
In Example 29, phenoxyacetic acid was replaced with (2-naphthoxy)acetic acid and (-)-2-(N-n-propylamino)-5-methoxy-tetralin was replaced with (±)-2-(N-n-propylamino)-5-methoxytetralin. The resulting oil was subjected to flash chromatography (Silica: 8:2 pet ether/EtOAc) and the product showed characteristic peaks at: NMR (300 MHz, CDCl3) δ7.8-6.6(m, 10H), 4.15(t, 2H), 3.8(S, 3H), 0.9(t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.ClC1C=CC(C=O)=CC=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:29](=O)[CH3:30])[CH:26]=[CH:27][CH:28]=1.C([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH:11][CH:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH3:30])=[CH:6][CH:7]=1
Reactant: COc1cccc(C(C)=O)c1
Reactant: NCCCc1ccc(Cl)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=Cc1ccc(Cl)cc1
Product: COc1cccc(C(C)NCCCc2ccc(Cl)cc2)c1

Procedure:
An equal molar amount of 3-(4-chlorophenyl)propylamine (prepared in a similar fashion from 4-chlorobenzaldehyde as above) 3′-methoxyacetophenone and 1.25 molar equivalents titanium(IV) isopropoxide were mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride (5 ml of I M, 5 mmol). Work-up and chromatography afforded N-[3-(4-chlorophenyl)propyl]-1-(3-methoxyphenyl)ethylamine, 6V, as an oil; m/z (rel. int.) 303 (M+, 8), 288 (91), 196 (4), 164 (10), 135 (100), 125 (61), 103 (21), 91 (21), 77 (18).
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](/B2OC(C)(C)C(C)(C)O2)\[CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[S:23][CH:24]=1.[F-].[Cs+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1(/[CH:6]=[C:7](\[C:20]2[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[S:23][CH:24]=2)/[CH2:8][OH:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1cc(Br)cs1
Reactant: CC1(C)OB(/C(=C/C2CCCC2)CO)OC1(C)C
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Product: CS(=O)(=O)c1cc(/C(=C\C2CCCC2)CO)cs1

Procedure:
According to method 20b was used (Z)-3-cyclopentyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (252 mg, 1.0 mmol), 4-Bromo-2-methanesulfonyl-thiophene (241 mg, 1.0 mmol), caesium fluoride ( 304 mg, 2.0 mmol) and tetrakis-(triphenylphosphin)-palladium(0) (58 mg, 0.05 mmol) to give 100 mg purified product. MS (m/e): 309.0 (M+Na).
Reaction SMILES: [CH3:1][N:2]([S:36]([CH3:39])(=[O:38])=[O:37])[C:3]1[C:8]([CH2:9][NH:10][C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([P:28](=[O:35])([O:32]CC)[O:29]CC)=[CH:24][CH:23]=3)[N:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.Cl>>[CH3:1][N:2]([S:36]([CH3:39])(=[O:38])=[O:37])[C:3]1[C:8]([CH2:9][NH:10][C:11]2[C:16]([C:17]([F:20])([F:18])[F:19])=[CH:15][N:14]=[C:13]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([P:28](=[O:29])([OH:32])[OH:35])=[CH:26][CH:27]=3)[N:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOP(=O)(OCC)c1ccc(Nc2ncc(C(F)(F)F)c(NCc3cccnc3N(C)S(C)(=O)=O)n2)cc1
Agent: Cl
Product: CN(c1ncccc1CNc1nc(Nc2ccc(P(=O)(O)O)cc2)ncc1C(F)(F)F)S(C)(=O)=O

Procedure:
Also prepared by heating diethyl [4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)phenyl]phosphonate (Example 2) at 100° C. with an excess of concentrated hydrochloric acid for 6 h. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC (MDP) afford the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)C>COCCCOCCCO>[N:16]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: C1CNCCN1
Agent: COCCCOCCCO
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc2c(N3CCNCC3)ccnc2c1
Yield: 42.7 %

Procedure:
4-Chloro-7-(trifluoromethyl)quinoline (2.3 g, 10 mmol) was dissolved in dipropyleneglycolmonomethyl ether (10 ml) together with piperazine (6.8 g, 0.1 mol) and glacial acetic acid (0.3 ml) and heated at reflux for 2 days. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica, gradient from ethylacetate to methanol containing 1% ammonia) to yield a yellow crystalline solid (1.2 g, 43%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][CH3:14])[C:11]2[C:10]([OH:12])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][O:4]1)[CH3:2].CN(C=O)C.Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=1.[Cl-].[NH4+]>O1CCCC1.O.[Fe]>[CH2:13]([C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:21]2[N:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=2)[CH2:5][O:4]1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCC1(CC)OCc2cccc(O)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CC)OCc2cccc(Oc3ccc(N)cn3)c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
To a solution of 3,3-diethyl-1H-isobenzofuran-4-ol (Intermediate 179, 0.03 g, 0.15 mmol) in dry DMF (3 ml) potassium carbonate (0.08 g, 0.6 mmol) and then 2-Chloro-5-Nitropyridine (0.026 g, 0.17 mmoli) were added and the reaction mixture was stirred for 2 hours at 80° C. After cooling the reaction mixture was quenched with water (1 ml), diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was dissolved in tetrahydrofuran (5 ml)/water (2.5 ml), iron (0.04 g, 0.75 mmol) and then ammonium chloride (0.4 g, 0.75 mmol) were added and the reaction mixture was stirred overnight at room temperature. The catalyst was filtered off and the residue was diluted with an aqueous saturated solution of NaHCO3 (5 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound (0.025 g) as a light yellow solid.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]COC)[C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.O>CO>[C:6]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:5]([OH:4])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:11]
Reactant: COCOc1cccc(OCOC)c1-c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1cccc(O)c1-c1ccccc1
Yield: 98.9 %

Procedure:
A solution of 16 (400 mg, 1.46 mmol) in MeOH (12.0 mL) at room temperature was treated dropwise with 3 M HCl (430 μL, 11.7 mmol), then heated to reflux for one hour. Water (15 mL) was added and the solution was extracted with EtOAc (3×20 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 17 as an orange amorphous solid (269 mg, 99%): 1H NMR (CDCl3, 400 MHz) 7.60 (d, J=7.6 Hz, 2H), 7.53-7.49 (m, 1H), 7.46-7.44 (m, 2H), 7.18 (t, J=8.2 Hz, 1H), 6.62 (d, J=8.2 Hz, 2H), 4.84 (s, 1H), 4.83 (s, 1H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:13])[CH3:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH2:14]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[O:14]=[C:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:13])[CH3:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)CCC2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of N-(2,3-dihydro-1H-inden-5-yl)acetamide (50 g, 0.29 mol) in 150 mL of acetic acid and 40 mL of actic anhydride was added a solution of chromium trioxide in a mixed solution (30 mL of water and 140 mL of acetic acid) dropwise at 10° C. by external cooling. After stirring overnight, the solution was poured into 2 L of ice water under vigorously stirring. The resulting solid was filtered, washed with cooled EtOH to give N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acetamide. 1H-NMR (300 MHz, CDCl3) δ ppm 7.90 (s, 1H), 7.66˜7.70 (m, 2H), 7.22˜7.25 (m, 1H), 3.09˜3.13 (m, 2H), 2.66˜2.70 (m, 2H), 2.22 (s, 3H);
Reaction SMILES: [OH:1][C:2]1([CH2:11][NH:12][C:13]([C:15]2[C:16]3[CH:17]=[CH:18][C:19](Cl)=[N:20][C:21]=3[CH:22]=[CH:23][C:24]=2[Cl:25])=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]2[CH2:10][CH2:9]2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:36][N:37]([CH3:43])[CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[OH:1][C:2]1([CH2:11][NH:12][C:13]([C:15]2[C:16]3[CH:17]=[CH:18][C:19]([N:40]4[CH2:41][CH2:42][CH:38]([N:37]([CH3:43])[CH3:36])[CH2:39]4)=[N:20][C:21]=3[CH:22]=[CH:23][C:24]=2[Cl:25])=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]2[CH2:10][CH2:9]2)[CH2:3]1
Reactant: CN(C)C1CCNC1
Reactant: O=C(NCC1(O)CCCC(C2CC2)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(C5CC5)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-cyclopropyl-cyclohexylmethyl)-amide, DIPEA and 3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.26 (s, 1H), 3.87 (t, 1H), 3.75 (m, 2H), 3.56 (m, 1H), 3.49 (m, 1H), 3.36 (m, 2H), 3.24 (m, 2H), 2.84 (m, 1H), 2.22 (s, 6H), 1.85 (m, 1H), 1.67 (m, 2H), 1.44-1.38 (m, 4H), 1.27 (m, 2H), 0.30 (m, 2H), 0.23 (m, 2H). m/z: 458 [M+H]
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1Br)=[O:2].C([O-])([O-])=O.[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.C1(C)C=CC=CC=1>[CH:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: O=CNCCc1ccccc1Br
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=CN1CCc2ccccc21
Temperature: 80 °C
Reaction time: 23 h
Yield: 98.5 %

Procedure:
A 15 mL resealable Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), N-formyl-2-(2-bromophenyl)ethylamine (229 mg, 1.00 mmol), K2CO3 (280 mg, 2.03 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %) and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 80° C. for 23 h. The resulting suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×10 cm, hexane-ethyl acetate 3:2, 15 mL fractions). Fractions 13-23 provided 145 mg (99% yield) of the desired product as a light yellow solid.