Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:20]([Br:21])=[CH:19][C:5]2[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]([C:9]3[CH2:13][CH2:12][CH2:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>C(Cl)Cl>[Br:21][C:20]1[C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:3][C:4]2[O:8][C:7]([C:9]3[CH2:13][CH2:12][CH2:11][CH:10]=3)=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]=2[CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(C2=CCCC2)oc2cc(N)c(Br)cc12
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C2=CCCC2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of ethyl 6-amino-5-bromo-2-(cyclopent-1-en-1-yl)benzofuran-3-carboxylate (3.63 g, 10.37 mmol) and pyridine (2.46 g, 31.1 mmol) in DCM (30 mL) was added dropwise methanesulfonyl chloride (2.37 g, 20.7 mmol) at 0° C., then the mixture was stirred at 25° C. overnight. 10% HCl(a.q.) was added, then the mixture was extracted with DCM (50 mL*3), dried over Na2SO4, and concentrated to give the product of ethyl 5-bromo-2-(cyclopent-1-en-1-yl)-6-(methylsulfonamido)benzofuran-3-carboxylate (4.3 g, yield: 96%). 1H-NMR (CDCl3, 400 MHz) δ 8.19 (s, 1H), 7.80 (s, 1H), 7.22 (t, J=2.0 Hz, 1H), 6.84 (s, 1H), 4.45 (q, J=7.2 Hz, 2H), 2.99 (s, 3H), 2.89˜2.94 (m, 2H), 2.62˜2.67 (m, 2H), 2.06 (t, J=7.6 Hz, 2H), 1.47 (t, J=7.2 Hz, 3H). MS (M+H)+: 428/430.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:34][C:35]1[CH:36]=[N:37][C:38]2[C:43]([C:44]=1[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53][CH3:54])[C:46]=1[O:55][CH3:56])=[CH:42][C:41]([Cl:57])=[CH:40][CH:39]=2>ClCCl>[C:15]([C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:13]=1[OH:14])[C:8]([NH:34][C:35]1[CH:36]=[N:37][C:38]2[C:43]([C:44]=1[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53][CH3:54])[C:46]=1[O:55][CH3:56])=[CH:42][C:41]([Cl:57])=[CH:40][CH:39]=2)=[O:10])([CH3:17])([CH3:16])[CH3:18]
Reactant: COc1ccc(-c2c(N)cnc3ccc(Cl)cc23)c(OC)c1OC
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(-c2c(NC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cnc3ccc(Cl)cc23)c(OC)c1OC
Temperature: 0 °C
Yield: 47.6 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-hydroxybenzoic acid (220 mg) in dichloromethane (20 ml) was dropwise added dicyclohexylcarbodiimide (DCC) (180 mg) under stirring at 0° C. The mixture was stirred at 0° C. for 15 minutes. Then, 3-amino-6-chloro-4-(2,3,4-trimethoxyphenyl) quinoline (250 mg) was added to this mixture. The resultant mixture was stirred at 0° C. for an hour and at room temperature for two days. After the residue was filtered off, the filtrate was diluted with water and extracted with dichloromethane. The dichloromethane layer was washed with an aqueous sodium hydroxide solution, diluted with hydrochloric acid and water in this order and dried (MgSO4). The solvent was removed and the residue was purified by a silica gel column chromatography with hexane-ethyl acetate (3:1, V/V), and then crystallized from isopropyl ether to obtain 3-(3,5-di-tert-butyl-4-hydroxybenzamido)-6-chloro-4-(2,3, 4-trimethoxyphenyl) quinoline (199 mg, 47.6%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)[CH:3]=1.[NH3:17]>CO>[S:14]1[CH2:15][CH2:16][CH:11]([C:4]2[CH:3]=[C:2]([NH2:17])[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)[CH2:12][CH2:13]1
Reactant: Clc1cc(C2CCSCC2)nc2ccnn12
Reactant: N
Solvent: CO
Product: Nc1cc(C2CCSCC2)nc2ccnn12
Temperature: 80 °C

Procedure:
A mixture of 7-chloro-5-(tetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine (Int-1c, 1.52 g, 6.0 mmol) in a solution of ammonia in MeOH (7 N, 20 mL) was heated in sealed vessel at 80° C. for 5 h. The reaction mixture was cooled down and concentrated. The residue was dried in high vacuum and used for the next step without further purification. LC/MS RT=0.92 Min (5 min method). Mass calculated for, M+H 235.09, observed 235.09.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][CH:4]1[C:3](=[O:8])[C:2]([CH3:1])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: BrBr
Reactant: CC1(c2ccccc2)CCCCC1=O
Solvent: ClC(Cl)Cl
Product: CC1(c2ccccc2)CCCC(Br)C1=O
Reaction time: 2 h
Yield: 101.1 %

Procedure:
A solution of 2-methyl-2-phenyl-cyclohexanone (0.94 g, 5.0 mmol) in chloroform (12 mL) at −5° C. was treated via rapid dropwise addition with a solution of bromine (0.26 mL, 5.1 mmol) in chloroform (6 mL) so as the reaction temperature maintaining below 5° C. The solution was kept at 0° C. for 2 h when the red color had disappeared. The mixture was concentrated under reduced pressure to give the crude title compound (1.35 g, 100%) as a brown oil which was used directly in the next step. MS ISP (m/e): 267.3 [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=7.22-7.42 (m, 3H), 7.13 (d, 2H), 4.70 (dd, 1H), 2.75 (m, 1H), 2.52 (m, 1H), 1.7-2.4 (m, 4H), 1.36 (s, 3H).
Reaction SMILES: [I-:1].[Na+].[C:3](=[O:18])([O:8][CH:9]1[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1)[O:4][CH:5](Cl)[CH3:6]>C(#N)C>[C:3](=[O:18])([O:8][CH:9]1[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1)[O:4][CH:5]([I:1])[CH3:6]
Reactant: CC1CC(OC(=O)OC(C)Cl)CC(C)(C)C1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC1CC(OC(=O)OC(C)I)CC(C)(C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetonitrile (250 ml) is warmed to 50° C. and 38 g of sodium iodide is added and dissolved, followed by addition of 14 g of 1-chloroethyl 3,3,5-trimethylcyclohexyl carbonate. The mixture is stirred for 2 hours, poured into 250 ml of ice-water and extracted with two 200-ml portions of ethyl acetate. The extracts are combined, washed with 150 ml of 5% aqueous sodium thiosulfate, 300 ml of water and 300 ml of saturated aqueous sodium chloride (twice) in that order and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure to to give the title compound as oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][C:15]([NH2:17])=[S:16])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:18]=[CH:19][CH:20]=[N:21][C:5]1=2.CI.[C:24](OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][S:16][C:15](=[NH:17])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][C:6]3[N:18]=[CH:19][CH:20]=[N:21][C:5]=3[N:4]([CH2:3][O:2][CH3:1])[C:9]=2[CH:10]=1
Reactant: COCN1c2cc(CC(N)=S)ccc2Sc2nccnc21
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COCN1c2cc(CC(=N)SC)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into 15 ml of a solution of 318 mg of (10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)thioacetamide in acetone was dropped 1.5 m of methyl iodide. After stirring at room temperature for 2 hours, the reaction mixture was distributed into ethyl acetate and an aqueous solution of potassium carbonate. The organic layer was extracted and the extract was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, 350 mg of the title compound was obtained as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:3]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:14][CH2:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:3]=1
Reactant: Cc1ccn(C(=O)OC(C)(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1ccc(CBr)n1
Temperature: 80 °C
Yield: 55.2 %

Procedure:
D5 (2 g, 10.97 mmol), N-bromosuccinimide (2.94 g, 16.46 mmol) and benzoyl peroxide (0.57 g, 1.65 mmol) were dissolved in carbon tetrachloride (40 ml) and heated to 80° C. for 3 h. The mixture was diluted with EtOAc (60 ml) and washed with saturated NaHCO3 solution and brine (100 ml each), dried (Na2SO4) and concentrated. Purification by column chromatography on silica (0-50% diethyl ether\40-60 pet. ether gradient) gave the title compound as a yellow oil (1.58 g). δH (CDCl3) 1.65 (9H, s), 4.49 (2H, s), 6.47 (1H, d), 8.03 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.CO[C:40](OC)([CH3:42])[CH3:41].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@@H:12]3[O:22][C:40]([CH3:42])([CH3:41])[O:21][C@@H:13]3[C@@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:15]2)=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:3]=1
Reactant: COC(C)(C)OC
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound is prepared by dissolving N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) in a 2:1 mixture of acetone and 2,2-dimethoxypropane with a catalytic amount of toluene-4-sulfonic acid, and stirring at room temperature overnight. The volatile components are removed under reduced pressure to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[C:12](=[O:20])[N:11]([CH2:21][C:22](O)=[O:23])[CH:10]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C:58]1[CH:59]=[C:60]2[C:73](=[CH:74][CH:75]=1)[CH2:72][C@@:62]1([C:70]3[C:65](=[N:66][CH:67]=[CH:68][CH:69]=3)[NH:64][C:63]1=[O:71])[CH2:61]2>CN(C=O)C>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH:10]2[N:11]([CH2:21][C:22](=[O:23])[NH:57][C:58]3[CH:59]=[C:60]4[C:73](=[CH:74][CH:75]=3)[CH2:72][C@:62]3([C:70]5[C:65](=[N:66][CH:67]=[CH:68][CH:69]=5)[NH:64][C:63]3=[O:71])[CH2:61]4)[C:12](=[O:20])[C:13]3([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]3)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Reactant: COc1cccc(C2CN(C(=O)OC(C)(C)C)C3(COCCOC3)C(=O)N2CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1cccc(C2CN(C(=O)OC(C)(C)C)C3(COCCOC3)C(=O)N2CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.44 g (0.81 mmol) 80% 2-(1-(tert-butoxycarbonyl)-3-(3-methoxyphenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecan-4-yl)ethanoic acid in 10 ml DMF were combined with 0.75 g (2.0 mmol) HATU and 0.34 ml (2.4 mmol) TEA and stirred for 10 min at RT. Then 0.25 g (0.98 mmol) (S)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one were added and the mixture was stirred overnight at RT. The reaction mixture was poured onto water. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.FC(F)(F)C(O)=O.[N+:18]([O-])([OH:20])=[O:19]>O>[OH:1][C:2]1[C:7]([N+:18]([O-:20])=[O:19])=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: CSc1nc(O)cc(O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CSc1nc(O)c([N+](=O)[O-])c(O)n1
Temperature: 23 °C
Reaction time: 5 h

Procedure:
A solution of 4,6-dihydroxy-2-methylthiopyrimidine (42 g, 0.257 mol) in trifluoroacetic acid (91 ml, 1.186 mol) was stirred at 23° C. and warmed until all solid had gone into solution. The reaction was stirred for five hours at 23° C. Next, fuming HNO3 (15 ml, 350 mmol) was added portion wise to the reaction mixture over 25 minutes at 0° C. The reaction was stirred for twenty hours at 23° C., and treated with H2O (at 23° C.) at 80% conversion (according LC-MS). The solid precipitate was captured via filteration giving 4,6-dihydroxy-2-methylthio-5-nitropyrimidine as a tan-colored solid. The crude solid was azeotroped with toluene to give 35 g of pale tan powdery solid. 1H-NMR: 300 MHz, (CD3OD, 300 MHz) d (ppm) 2.63 (s, 3H). LCMS-ESI+: calc'd for C5H4N3O4S: 202.0 (M−H−); Found: 202.0 (M−H−).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:37])[C@@H:7]([NH:12][C:13]([C:15]1[N:16]=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:19]=12)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])(=O)[CH3:2].C1CCN2C(=NCCC2)CC1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:10][C:8]([CH3:9])([CH3:11])[C@H:7]([NH:12][C:13]([C:15]1[N:16]=[C:17]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:20][C:19]=12)=[O:14])[C:6]1[O:37][C:1]([CH3:2])=[N:4][N:5]=1
Reactant: CC(=O)NNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1nnc([C@@H](NC(=O)c2nc(-c3ccccc3)n3c2CN(C(=O)OC(C)(C)C)CC3)C(C)(C)C)o1
Temperature: 150 °C
Yield: 0.1 %

Procedure:
The intermediate 14D (48 mg, 94 mmol) was taken up in THF (1 mL) and added to a 2 mL microwave reaction vial. DBU (21 μL, 0.14 mmol) was added to the reaction, followed by the Burgess reagent (112 mg, 468 mmol). The vial was capped and the reaction mixture was heated to 150° C. for 5 minutes, after which some starting material still remained. Additional Burgess reagent (1 equiv) was added and the reaction was heated to 150° C. for 10 minutes. LC/MS showed that the starting material was consumed. The reaction was diluted with of saturated aqueous NaHCO3 (1 mL) and EtOAc (2 mL). The organic layer was removed and the aqueous layer extracted with EtOAc (2 mL). The organic layers were combined, dried with anhydrous Na2SO4, filtered and evaporated. The residue was purified by Flash chromatography on silica using a gradient from 10% EtOAc/Hexanes to 60% EtOAc/Hexanes. This provided intermediate 14E as a clear oil (25 mg, 54% yield). LCMS (+ESI) m/z 495.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[F:8].C[CH2:11][O:12][CH2:13][CH3:14]>[Ni]>[F:1][C:2]1[CH:3]=[C:4]([C:2]2[CH:3]=[CH:14][C:13]([O:12][CH3:11])=[CH:6][CH:7]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(I)cc1F
Reactant: CCOCC
Agent: [Ni]
Product: COc1ccc(-c2ccc(F)c(F)c2)cc1

Procedure:
A p-methoxyphenylmagnesium halide as a Grignard reagent, obtained from a p-halogenoanisole (IV), is reacted with a 3,4-difluoro-1-iodobenzene (V) at a low temperature in the vicinity of 0° C. in an ether solvent in the presence of Ni catalyst to obtain a 3,4-difluoro-4'-methoxybiphenyl (VI), which is then reacted with HBr to obtain (III). These reactions are expressed by the following reaction equations: ##STR6##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:15][C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:17]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:15][C@@H:16]1[CH2:17][N:18]([C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH2:19][CH2:20][N:21]1[C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)c1ccnc(Cl)n1
Reactant: C[C@@H]1CN(c2ccc(S(C)(=O)=O)cc2)CCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2ccc(S(C)(=O)=O)cc2)CCN1c1nccc(C(=O)OC(C)(C)C)n1
Temperature: 100 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
Tert-butyl 2-chloropyrimidine-4-carboxylate (70 mg, 0.326 mmol) and (R)-3-methyl-1-(4-(methylsulfonyl)phenyl)piperazine (166 mg, 0.652 mmol) were dissolved in acetonitrile (2 ml), followed by addition of N,N-diisopropylethylamine (0.11 ml, 0.652 mmol), and then the resulting liquid was stirred at 100° C. under nitrogen stream for 24 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (50% EtOAc/Hexanes), to obtain 120 mg of pale yellow solid (85%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)o1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cccc(F)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.06 min; [M+H]+=409.11.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:20]3[CH2:21][CH2:22][CH:23]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:19]3[CH2:18][CH2:17][O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:24]([CH:23]1[N:19]2[CH:20]([CH:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[O:16][CH2:17][CH2:18]2)[CH2:21][CH2:22]1)[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(CCC2CCC3C(c4ccc(OCc5ccccc5)cc4)OCCN23)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(C2OCCN3C(CCc4ccccc4)CCC23)cc1
Yield: 35.1 %

Procedure:
(1RS,6SR,8aRS)-1-(4-Benzyloxy-phenyl)-6-phenethyl-hexahydro-pyrrolo [2,1-c][1,4]oxazine (0.09 g, 0.22 mmol) was dissolved in MeOH (5 ml) and hydrogenated in the presence of Pd on C at room temperature and at atmospheric pressure for 4 hours. After filtration and evaporation of the solvent the residue was chromatographed over silica gel (CH2Cl2 --MeOH 19:1) to provide (1RS,6SR,8aRS)-4-(6-phenethyl-hexahydro-pyrrolo[2,1-c][1,4]oxazin-1-yl)-phenol (25 mg, 35%) as a pink solid, m.p. 170-172° C. MS: m/e=324.3 (M+H+). Following the general method of example 35 the compounds of examples 36 to example 38 were prepared.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].OP([O-])([O-])=O.[Na+].[Na+].[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C(Cl)Cl>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccccc1F
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.3 %

Procedure:
To a solution of acryloyl chloride (0.70 mL, 8.63 mmol) and sodium phosphate dibasic (2.45 g, 17.26 mmol) in anhydrous methylene chloride (18.0 mL) at 0° C. was added dropwise 2-fluoroaniline (0.834 mL, 8.63 mmol). The reaction mixture was stirred at room temperature for 12 h. It was then filtered over a celite pad, washed with methylene chloride (50 mL) and concentrated to afford N-(2-fluorophenyl)acrylamide (C-4) as a white solid (0.959 g, 68% yield). MS (M+1): m/e 166. This material was used for the next step with no additional purification.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[NH2:23][CH2:24][CH2:25][CH2:26][NH2:27].O>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[N:23]3[CH2:24][CH2:25][CH2:26][NH:27][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: NCCCN
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccc(Cl)cc2C2(c3ccccc3)NCCCN12
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of 1.89 g of 2-trichloroacetamido-5-chlorobenzophenone in 50 ml of ethanol was added 2.22 g of 1,3-diaminopropane, and the resultant mixture was allowed to stand at room temperature overnight. Then, the reaction mixture was poured into 300 ml of water, and the precipitate thus formed was separated by filtration, washed with ether and dried to give 1.25 g of 10-chloro-1,2,3,4,7,11b-hexahydro-11b-phenyl-6H-pyrimido[1,2-C]quinazolin-6-one, having a melting point of 275° - 276°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([O:15]C)=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.[OH-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([OH:15])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(OC)cc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(c(C(=O)O)c1)CCCC2
Yield: 94.8 %

Procedure:
A solution of methyl 3-methoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylate (0.90 g, 4.09 mmol) in THF (50 mL), water (20 mL) and 1N NaOH (8.6 mL, 8.6 mmol) was stirred for 3 days at room temperature. The THF was evaporated and the mixture acidified to pH 1 with 1N HCl. The resulting precipitate was extracted with EtOAc, dried (MgSO4), filtered and concentrated to give the acid as a white solid (0.80 g, 95%). 1H NMR (DMSO) δ 12.79 (s, 1H), 7.09 (d, 1H), 6.82 (d, 1H), 3.73 (s, 3H), 2.86 (s, 2H), 2.74 (s, 2H), 1.68 (m, 4H); MS m/z 205 (M−H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[C:17](=O)[NH:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:46]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[C:17]([Cl:46])=[N:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc3nc[nH]c(=O)c23)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc3ncnc(Cl)c23)CC1

Procedure:
5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one (0.31 g) was reacted with triphenylphosphine and carbon tetrachloride to give 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chloroquinazoline (0.156 g); NM Spectrum: (CDCl3) 1.5 (s, 9H), 1.9–2.1 (m, 4H), 3.5–3.8 (m, 4H), 4.8 (m, 1H), 7.05 (d, 1H), 7.65 (d, 1H), 7.82 (m, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 364 and 366; and
Reaction SMILES: [C:1](=[O:7])=[N:2][S:3]([Cl:6])(=[O:5])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])=[CH:11][C:10]=1[N+:25]([O-:27])=[O:26]>C1(C)C=CC=CC=1>[Cl:6][S:3]([NH:2][C:1](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])=[CH:11][C:10]=1[N+:25]([O-:27])=[O:26])(=[O:5])=[O:4]
Reactant: Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1[N+](=O)[O-]
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1[N+](=O)[O-])NS(=O)(=O)Cl

Procedure:
30 ml of N-chlorosulfonyl isocyanate dissolved in 70 ml of toluene are rapidly added dropwise, at +10° C., to 88.2 g of 2-amino-5-phenoxysulfonylnitrobenzene in 750 ml of toluene. The mixture is stirred for a further hour while cooling, and the precipitate is filtered off with suction, washed with diisopropyl ether and dried in a desiccator over potassium hydroxide. 88 g of the 2-(3-chlorosulfonylureido)-5-phenoxysulfonylnitrobenzene produced are introduced, with stirring and cooling, into 800 ml of 1N HCl. After 30 minutes, the clear solution is briefly warmed to 80° C. (precipitation) and then left to stand. After cooling down, the solid is filtered off with suction and washed with water to neutrality, melting point 190° C.