Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)[CH:4]([CH3:6])[CH3:5])C.Br[CH2:11][CH2:12][CH3:13].[NH2:14][CH2:15][C:16]1[N:20]=[C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][C@H:26]4[C:25]=23)[O:18][N:17]=1>CN(C)C=O>[CH2:11]([N:14]([CH2:15][C:16]1[N:20]=[C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][C@H:26]4[C:25]=23)[O:18][N:17]=1)[CH2:5][CH2:4][CH3:6])[CH2:12][CH3:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCBr
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)n1
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)n1
Reaction time: 12 h
Yield: 52.3 %

Procedure:
4 ml (8.6 mmol) of N-ethyldiisopropylamine and 1.1 ml (12 mmol) of 1-bromopropane were added to a solution of 600 mg (1.9 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-11,11a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 20 ml of dimethylformamide and the mixture was stirred at 70° for 12 hours. The reaction solution was subsequently evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed three times with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:1). There were obtained 410 mg (54%) of (S)-1-(dipropylaminomethyl-1,2,4-oxadiazol-5-yl)-11,11 a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.55 (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:1).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:32])[O:6][N:5]=1)[CH3:3].[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:49]=[CH:50][C:51]([C:52]([N:29]4[CH2:30][CH2:31][CH:26]([N:12]5[C:13](=[O:25])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:7]6[O:6][N:5]=[C:4]([CH2:2][CH3:3])[CH:8]=6)[C:11]5=[O:32])[CH2:27][CH2:28]4)=[O:53])=[CH:55][CH:56]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34]
Reactant: CCc1cc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)on1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5cc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(3-Ethylisoxazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (200 mg; compound B28) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (168 mg; compound C10) and HBTU (191 mg) in DCM (10 ml) in the presence of DIPEA (0.29 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 3/1 to 0/1 (v/v)] and preparative HPLC as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:19][C:18]2[N:17]=[C:16]3[C:12]([C:13]([NH2:23])=[C:14]([C:20](=[O:22])[NH2:21])[S:15]3)=[C:11]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C([Cl:32])(=O)C>CO>[ClH:32].[NH2:23][C:13]1[C:12]2[C:16](=[N:17][C:18]3[CH2:19][NH:8][CH2:9][C:10]=3[C:11]=2[C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[S:15][C:14]=1[C:20]([NH2:21])=[O:22]
Reactant: CC(C)(C)OC(=O)N1Cc2nc3sc(C(N)=O)c(N)c3c(-c3cccs3)c2C1
Reactant: CC(=O)Cl
Solvent: CO
Product: Cl
Product: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CNC3
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To a suspension of 3-amino-2-carbamoyl-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-6-carboxylic acid tert-butyl ester (4 g, 9.6 mmol)) in 70 ml of anhydrous methanol was added dropwise 7 ml of acetyl chloride under argon. The resulting mixture was stirred for 48 hours at room temperature. The solid was filtered and washed with methanol to give 3.14 g (93%) of the yellow product as its hydrochloride salt. 1H-NMR (300 MHz, DMSO-d6): δ 10.20 (brs, 2H), 7.96 (dd, J=1.2, 5.1 Hz, 1H), 7.36 (dd, J=1.2, 3.6 Hz, 1H), 7.32 (brs, 2H), 7.31 (dd, J=3.6, 5.1 Hz, 1H), 6.02 (brs, 2H), 4.63 (s, 2H), 4.42 (s, 2H). ES MS m/z 317 (M+H)+, 315 (M−H)−.
Reaction SMILES: [OH-].[K+].[I:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[CH:6][C:5]=1[OH:12].[F:13][C:14](F)([F:22])S(OC(F)F)(=O)=O>C(#N)C.O>[F:13][CH:14]([F:22])[O:12][C:5]1[C:4]([I:3])=[CH:9][C:8]([O:10][CH3:11])=[N:7][CH:6]=1
Reactant: O=S(=O)(OC(F)F)C(F)(F)F
Reactant: COc1cc(I)c(O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1cc(I)c(OC(F)F)cn1
Reaction time: 0.03 h

Procedure:
4.8 ml of aqueous potassium hydroxide solution (6M) were added to a solution of 600 mg (purity 93%, 2.22 mmol) of 4-iodo-6-methoxypyridin-3-ol in 4.8 ml of acetonitrile, the mixture was cooled in an ice bath and 863 μl (purity 75%, 3.56 mmol, 1.6 eq.) of difluoromethyl trifluoromethanesulphonate [Angew. Chem. Int. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009, 130, 667-670] were added with vigorous stirring. The reaction mixture was stirred for 2 min and diluted with 33 ml of water. The aqueous phase was extracted twice with in each case 40 ml of diethyl ether. The combined organic phases were dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The crude product was purified by flash chromatography (IR-50SI, petroleum ether/ethyl acetate 12-20%). Yield: 407 mg (purity 90%, 55% of theory)
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH3:30])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH3:30])[S:32]([CH3:31])(=[O:34])=[O:33])=[CH:26][CH:27]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CNCc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
A mixture of the compound (100 mg) obtained in Example 4, methanesulfonyl chloride (30 mg), triethylamine (76 mg) and tetrahydrofuran (2 ml) was stirred at 0° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, and washed with water. The precipitate was collected by filtration to give the title compound (32 mg) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:16]=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:16]=[N:15]2)[N:3]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1cc(-c2ccccc2C)cn1
Product: Cc1ccccc1-c1cnn(CCC#Cc2cccc(CF)n2)c1
Yield: 30 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.26 mmol) and 1-but-3-ynyl-4-o-tolyl-1H-pyrazole (50 mg, 0.24 mmol, Example 142(A)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 23 mg (72 μmol, 30%) of 2-(fluoromethyl)-6-(4-(4-o-tolyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellow solid with a purity of 81%.
Reaction SMILES: C1([NH:9][C:10]([NH2:12])=[O:11])C=CC(C)=CC=1C.C(#N)C.[C:16](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH3:17].[CH3:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH2:28]>CCCCCC>[CH3:17][C:16]([NH:9][C:10]([NH:12][C:27]([CH3:26])([CH3:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:11])([CH3:18])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(Cl)c1ccccc1
Reactant: C=C(C)c1ccccc1
Reactant: Cc1ccc(NC(N)=O)c(C)c1
Solvent: CC#N
Solvent: CCCCCC
Product: CC(C)(NC(=O)NC(C)(C)c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
12.4 parts of 2,4-xylylurea was suspended in 50 parts of acetonitrile, and 7.7 parts of cumyl chloride and 24 parts of α-methylstyrene were added. With stirring, they were reacted at 40° C. for 6 hours. After allowing the reaction mixture to stand for one day, 50 parts of n-hexane was added. The mixture was further allowed to stand overnight. The precipitated crystals were collected, and recrystallized from 60% methanol to afford 12.5 parts of N-(α,α-dimethylbenzyl)-N'-(2,4,urea (III: R=--C6H3 (CH3)2 --2,4) having a melting point of 163° C.
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:38][OH:39].C[O-].[Na+]>C(O)(=O)C>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([O:39][CH3:38])[N:21]=1
Reactant: CO
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 98 %

Procedure:
To a 250 mL dry round-bottomed flask was charged (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (12, 7.50 g, 14.26 mmol) Anhydrous methanol (30 mL) was added and a white suspension was formed. At 50° C., a solution of sodium methoxide in methanol (25%, 19.7 mL, 64.17 mmol) was added via a dry syringe under a nitrogen atmosphere. A white cloudy reaction mixture was formed. After 3.5 h at 50° C., the reaction was complete with no starting material left as shown by TLC test. The mixture was cooled down to room temperature and neutralized by addition of glacial acetic acid (3 mL). A white solid was filtered out and washed with methanol (3×5 mL). The filtrate was mixed with 20 g of silica gel and concentrated to dryness. The mixture was loaded in line with a silica gel cartridge and separated via column chromatography using a gradient of methanol in dichloromethane 0 to 15% MeOH. The product eluted out at 12% methanol in dichloromethane. The product containing fractions were combined, concentrated under reduced pressure and dried under vacuum (0.2 mmHg, 50° C., 24 h) to a white powder solid (4.45 g, 98% yield), mp 199-202° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](/[C:12](/[CH3:24])=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([CH3:25])[CH2:4][CH2:3]1.[OH-].[K+]>C(O)C.O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](/[C:12](/[CH3:24])=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([CH3:25])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)N(C)CCN3C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)N(C)CCN2C
Yield: 78.3 %

Procedure:
600 mg of this ester were converted into the free acid by reaction with a solution of 1.5 g of potassium hydroxide in 25 ml of ethanol and 10 ml of water at 50° C. during 4 hours. After recrystallization from ethyl acetate/hexane, there were obtained 450 mg of p-[(E)-2-(1,2,3,4-tetrahydro-1,4-dimethyl-6-quinoxalinyl)propenyl]benzoic acid in the form of orange crystals, melting point 203°-205° C.
Reaction SMILES: [C:1]([NH:6][C:7]1[C:16](=[O:17])[C:15]2[N:14]=[C:13]([CH3:18])[CH:12]=[CH:11][C:10]=2[C:9](=[O:19])[CH:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Se](=O)=[O:21]>O>[C:1]([NH:6][C:7]1[C:16](=[O:17])[C:15]2[N:14]=[C:13]([CH:18]=[O:21])[CH:12]=[CH:11][C:10]=2[C:9](=[O:19])[CH:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=[Se]=O
Reactant: CCCC(=O)NC1=CC(=O)c2ccc(C)nc2C1=O
Solvent: O
Product: CCCC(=O)NC1=CC(=O)c2ccc(C=O)nc2C1=O
Reaction time: 33.5 h
Yield: 65 %

Procedure:
In a 25 ml. round-bottomed flask equipped with a magnetic bar, water-cooled reflux condenser, and an argon filled balloon, 7-butyramido-2-methylquinoline-5,8-dione (30) (prepared as described in Example 30) (0.516 g., 2 mmol), selenium dioxide (0.255 g., 2.3 mmol), 12 ml. of dried, distilled 1,4-dioxane, and 0.25 ml. of water were stirred and slowly heated to reflux over a two-hour period. The reaction was monitored by TLC and found to be complete after 33.5 hours. The selenium metal was allowed to settle, and the supernatant solution was pipetted off and filtered. 1,4-Dioxane (10 ml.) was added to the residue, stirred and refluxed for five minutes. The entire mixture was filtered and the selenium was washed with dichloromethane (10 ml.). All filtrates were combined and stored at 4EC overnight. This solution was diluted with 50 ml of dichloromethane and washed with a 3% sodium bicarbonate solution (2×50 ml.). The organic layer was dried with magnesium sulfate and rotoevaporated to give a pale yellow product. The solid was dried under vacuum overnight and weighed 0.356 g. (yield of 65%). The product was recrystallized from ethyl acetate: mp. 208-210E C; 1H NMR (CDCl3) * 1.02 (3H, t, J=7.4 Hz, C-7NHCOCH2CH2CH3),1.70 -1.89 (2H, m, 7NHCOCH2CH2CH3), 2.52 (2H, t, J=7.4 Hz, 7NHCOCH2CH2CH3), 8.06 (1 H, s, C-6H), 8.31 (1 H, d, J=8.0 Hz, C-3H), 8.39 (1H, br. s, C-7NH), 8.61 (1H, d, J=8.0 Hz, C4H), 10.28 (1H, s, C-2CHO); IR (KBr) vmax 3299, 3081, 2966, 2935, 2876, 1723, 1694, 1638, 1606, 1505 cm-1 ; EIMS, m/e (relative intensity) 272 (54), 202 (36), 175 (9); HRMS, m/e for C14H12N2O4 calculated 272.079707, found 272.078696; analysis for C14H12N2O4 calculated C, 61.76; H, 4.44; N, 10.29; found C, 61.31; H, 4.36; N, 9.94.
Reaction SMILES: Cl.[CH2:2]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=4)[CH:18]=[N:17][CH:16]=3)[NH:10][C:9]=2[C:8](=[O:29])[N:7]([CH3:30])[C:6]1=[O:31])[CH:3]=[CH2:4].[OH-:32].[Na+].OO>C1COCC1>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[CH:18]=[N:17][CH:16]=[C:15]2[CH2:14][C:11]1[NH:10][C:9]2[C:8](=[O:29])[N:7]([CH3:30])[C:6](=[O:31])[N:5]([CH2:2][CH2:3][CH2:4][OH:32])[C:13]=2[N:12]=1
Reactant: [OH-]
Reactant: C=CCn1c(=O)n(C)c(=O)c2[nH]c(Cc3cncc4cc(OC)c(OC)cc34)nc21
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CCCO)c2cc1OC
Temperature: 50 °C

Procedure:
A suspension of the product of Example 13, 3-allyl-8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione hydrochloride salt (0.760 g, 1.87 mmol), 9-borabicyclo[2.2.0 ]nonane (0.5M THF solution, 18.7 ml, 9.35 mmol) and diisopropylethylarine (0.33 ml, 1.89 mmol) in THF (9 ml) is heated to reflux for 2.5 hours. Sodium hydroxide (4M aqueous solution, 6 ml) and hydrogen peroxide (27.5%, 3 ml) are added sequentially and the reaction heated at 50° C. for 1.5 hours. After evaporation, the crude product is purified by flash chromatography (19:1 CH2Cl2:-methanol elultion,) and triturated with water to afford 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-(3-hydroxy-propyl)-1-methyl-3,7-dihydro-purine-2,6-dione, [MH]+ 426.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=CC(CCC(O)=O)=CC=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.ClC1C=CC(C2N(CC3C=C(C=CC=3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=C(OCC2CCCC2)C=1.[CH3:73][O:74][C:75](=[O:84])[C:76]1[CH:81]=[CH:80][C:79]([CH2:82]Br)=[CH:78][CH:77]=1>>[CH3:73][O:74][C:75](=[O:84])[C:76]1[CH:81]=[CH:80][C:79]([CH2:82][N:12]2[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:31][CH3:32])=[CH:78][CH:77]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Product: COC(=O)c1ccc(Cn2c(-c3ccc(Cl)cc3OC)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 4-bromomethyl-benzoic acid methyl ester (CAS Reg. No. 2417-72-3). Brown solid (33%). MS (Turbo Spray): m/z=443.2 (M+H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[CH2:31][C:30]2[C@H:25]([CH2:26][CH2:27][C:28](=[O:32])[CH:29]=2)[C@@H:24]2[C@@H:15]1[C@H:16]1[C@@:20]([CH2:22][CH2:23]2)([CH3:21])[C:19](=[O:33])[CH2:18][CH2:17]1)(C(C)(C)C)(C)C.C(O)(=O)C>CO.O>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[CH2:31][C:30]2[C@H:25]([CH2:26][CH2:27][C:28](=[O:32])[CH:29]=2)[C@@H:24]2[C@@H:15]1[C@H:16]1[C@@:20]([CH2:22][CH2:23]2)([CH3:21])[C:19](=[O:33])[CH2:18][CH2:17]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Yield: 99 %

Procedure:
A solution of 125.4 g of 7α-(5-tert-butyl-dimethylsilyloxypentyl)-estr-4-ene-3,17-dione in 625 ml of methanol and 347 ml of water is stirred with 694 ml of glacial acetic acid for 2.5 hours at 50° C. After concentration by evaporation at 60° C. in a vacuum, 94.1 g of crude 7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione is obtained as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].O>O1CCOCC1.C(OO)(C)(C)C.[Br-].[Al+3].[Br-].[Br-]>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: CC(C)(C)OO
Agent: [Al+3]
Agent: [Br-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
In a 50 ml flask, there were charged (-)-cis-chrysanthemic acid (2.0 g), dioxane (17.5) and t-butyl hydroperoxide (0.011 g) under nitrogen. A solution of aluminum bromide (0.032 g) in dioxane (0.5 g) was added thereto at 15°-20° C. with stirring. After 30 minutes, water (0.5 g) was added to the reaction mixture with stirring. The reaction mixture was treated in the same manner as described in Example 1 and 1.91 g of chrysanthemic acid was obtained. The composition was as follows: (+)-cis, 3.3%; (-)-cis, 4.2%; (+)-trans, 46.2%; (-)-trans, 46.2%.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:40][CH:39]=3)=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[C:13]([NH:15][C@@H:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:17])=[O:14])=O)C1C=CC=CC=1.C(O)(=O)C>C1COCC1.[Pd].CCO>[NH2:11][C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:40][CH:39]=3)=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[C:13]([NH:15][C@@H:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH3:17])=[O:14]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Yield: 81.4 %

Procedure:
Prepared using General Procedure 18: To a stirred solution of tert-butyl ((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate (860 mg, 1.238 mmol) in THF (30 mL) was added palladium on carbon (10 wt %) as a slurry in EtOH (4 mL). To this mixture was added acetic acid (1 mL) and the reaction mixture was hydrogenated at 4 bar pressure at room temperature. The reaction mixture was diluted with THF (50 mL) and filtered through Celite. The crude product was loaded onto a column in 5% AcOH in MeOH/THF. The column was washed with MeOH/THF/DCM and then the product was eluted with 0.7 M ammonia in MeOH/THF/DCM. The resultant mixture was concentrated in vacuo to afford 565 mg (77%) of tert-butyl ((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate INT-24 as a yellow solid. LCMS-ESI (m/z) calculated for C33H44N4O4: 560.3; no m/z observed, tR=2.61 min (Method 11).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[H-].[Na+].[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1.CN([CH:35]=[O:36])C>O>[F:18][C:19]([F:31])([F:30])[C:35]([OH:36])=[O:2].[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:30])[F:31])[CH:21]=1)(=[O:28])=[O:27])[CH:7]=[CH:6]2
Reactant: CN(C)C=O
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cccc(C(F)(F)F)c2)c1CN(C)C
Product: O=C(O)C(F)(F)F
Reaction time: 0.5 h

Procedure:
(5-Methoxy-1H-indol-4-ylmethyl)-dimethyl-amine (23.5 mg, 0.115 mmol; Intermediate 79) was distributed in two portions in DMF, NaH (60%) added and the mixture was stirred for 30 min before adding 3-trifluoromethylbenzene-sulfonyl chloride (56.3 mg, 0.230 mmol). The reaction mixture was diluted with water and extracted with DCM, dried and concentrated. This residue was purified by preparative HPLC. Yield: 7 mg. MS (ESI+) for C19H19F3N2O3S m/z 413 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[N+]([C:14]1[CH:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18][C:19]=1Br)([O-])=O.NC1C(N)=C(NC2C=CC=CC=2)C=CC=1>Cl>[CH3:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]2[C:5](=[N:9][C:19]3[C:18]([N:10]=2)=[CH:17][C:16]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[CH:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Br
Reactant: Cc1cc(N)c(N)cc1C
Agent: Cl
Agent: Nc1cccc(Nc2ccccc2)c1N
Product: Cc1cc2nc3ccc(C(F)(F)F)cc3nc2cc1C

Procedure:
The 2,3-dimethyl-7-trifluoromethylphenazine was prepared in a 3-step process, starting with 4,5-dimethyl-1,2-phenylenediamine and 3-nitro-4-bromobenzotrifluoride. The nucleophilic substitution product being the biarylamine was then reduced with stannous chloride in conc. HCl to the diamino diphenylamine.