Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH3:30][C:31]1[S:32][CH:33]=[C:34]([CH2:36][N:37]2[C:42]3[CH:43]=[C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[S:45][C:41]=3[C:40](=[O:52])[N:39]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[C:38]2=[O:59])[N:35]=1.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>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:56]4[CH2:57][CH2:58][CH:53]([N:39]5[C:40](=[O:52])[C:41]6[S:45][C:44]([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=7)=[CH:43][C:42]=6[N:37]([CH2:36][C:34]6[N:35]=[C:31]([CH3:30])[S:32][CH:33]=6)[C:38]5=[O:59])[CH2:54][CH2:55]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: Cc1nc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)cs1
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(Cc5csc(C)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
The title compound is prepared analogously as described for example 1 using 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10), 1-[(2-methyl-1,3-thiazol-4-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B35), HBTU (167 mg), DIPEA (0.28 ml) and DCM (3 ml). The crude product is purified by flash column chromatography for three consecutive times (amino phase silica gel, eluent: EtOAc) to yield the title compound as a solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@@H:16]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:15][C@@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[Br:32]N1C(C)(C)C(=O)N(Br)[C:34]1=[O:35]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@@H:16]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:15][C@@H:6]1[O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][Br:32])=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH3:34][OH:35]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(=O)OC[C@H]1O[C@H](Oc2ccc(C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@H](Oc2ccc(CBr)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Product: CO
Yield: 422.9 %
Yield: 76 %

Procedure:
1.4 g (3.2 mmoles) of 4-methylphenyl 2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside (71) and 0.46 g (1.6 mmole) of 1,3-dibromo 5,5-dimethylhydantoine are added in 100 ml of carbone tetrachloride, and the mixture est refluxed under irradiation with light (1 000 W) for 15 minutes. After cooling, the reaction medium is filtered and the filtrate is then evaporated to dryness. 3.5 g of 4-bromomethylphenyl 2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside (72) are isolated by crystallization from methanol (yield=76%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=C(C#N)[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1.[ClH:21].[C:22]([OH:25])(=[O:24])[CH3:23]>>[ClH:21].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=[C:23]([C:22]([OH:25])=[O:24])[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc(N)cc1C=C2
Agent: Cl
Product: Nc1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2(=O)=O

Procedure:
415 Mg. 8-amino-3-cyanodibenzo[b,f]thiepin-5,5-dioxide is suspended in a mixture of 15 cc. concentrated hydrochloric acid and 15 cc. acetic acid and refluxed for 24 hours. The reaction mixture is evaporated to dryness and the residue collected and dried at 100° C. at 0.5 mm./Hg. to yield 454 mg. pure product, m.p. 280° C.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:5](C(O)=O)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[C:22]([Cl:25])(Cl)=[O:23].C(OC)(=O)C1C=CC(C(OC)=O)=CC=1.[Cl:40]CCl>>[C:22]([Cl:25])(=[O:23])[C:5]1[CH:9]=[CH:10][C:2]([C:1]([Cl:40])=[O:12])=[CH:3][CH:4]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)Cl
Agent: COC(=O)c1ccc(C(=O)OC)cc1
Solvent: CN(C)c1ccccc1
Product: O=C(Cl)c1ccc(C(=O)Cl)cc1
Yield: 90.2 %

Procedure:
Following the general procedure in Example 1 for the preparation of the diacid chloride, 8.93 parts of terephthalic acid were added to a mixture of 16.47 parts of N,N-dimethyl aniline and 12.8 parts phosgene in 200 parts dry dichloromethane at 25° to 30° C. The ratio of equivalents of dimethylaniline base/COOH acid group was 1.26. After carrying out the reaction and esterifying the resulting diacid chloride by the procedure described in Example 1, 9.87 parts of a solid containing 95.4% dimethyl terephthalate was obtained corresponding to a 90.2% yield of theory of terephthaloyl chloride formed initially in the reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21]O)=[O:18])=[N:9]2)=[N:6][CH:7]=1.BrC1C=CC(N2C(C(F)(F)F)=CC(C(O)=O)=N2)=NC=1.C(Cl)(=O)C(Cl)=O.NC(C)(C)CO>C(Cl)Cl.O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]3[O:18][CH2:23][C:20]([CH3:21])([CH3:24])[N:19]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(CO)NC(=O)c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Agent: CC(C)(N)CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)COC(c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)=N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Step-1: 1-(5-Bromopyridin-2-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide: To (0° C.) cooled solution of 1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (500 mg, 1.48 mmol), in DCM (20 mL) was added oxalyl chloride (391 μL, 4.46 mmol) followed by catalytic amount of DMF. The resulting mixture was stirred at room temperature for 3 h. The solvent and excess of oxalyl chloride was then removed under vacuum and the resulting residue was dissloved in DCM (10 mL). A solution of 2-amino-2-methylpropan-1-ol (0.35 mL, 3.72 mmol) in DCM (5 mL) was then added to the above solution drop-wise at 0° C. and the resulting mixture was warmed to room temperature and then continued stirring at the same temperature for 18 h. Water (10 mL) was added to the above reaction followed by DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were washed with bine (10 mL), dried (anhydrous Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography to afford 600 mg (99%) of the title compound as white solid. 1HNMR (400 MHz, CDCl3) δ 8.61 (d, J=2.0 Hz, 1H), 8.04 (dd, J=2.0 & 8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 6.96 (s, 1H, D2O exchangeable), 3.73 (s, 2H), 1.44 (s, 6H) ; ESI-MS (m/z) 407, 409 [(MH)+, Br79,81].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=1>CC(O)C>[ClH:19].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([Br:22])=[CH:24][C:25]=3[F:30])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCc1ccccc1
Product: Cl
Yield: 69.3 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline (8.35 g, 27.8 mmol), (prepared as described for the starting material in Example 1), and 4-bromo-2-fluoroaniline (5.65 g, 29.7 mmol) in 2-propanol (200 ml) was heated at reflux for 4 hours. The resulting precipitate was collected by filtration, washed with 2-propanol and then ether and dried under vacuum to give 7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (9.46 g, 78%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)cn1
Reactant: Nc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(COc2ccc(Nc3ccccn3)nc2)cc1
Yield: 91.4 %

Procedure:
Compound I (370 mg, 1.40 mmol), 2-aminopyridine (145 mg, 1.54 mmol), tBuOK (235 mg, 2.10 mmol), (±)-BINAP (35 mg, 0.01 mmol) and Pd2(dba)3 (32 mg, 0.006 mmol) were stirred in toluene (5 mL) at 90° C. under Ar(g) for 17 h. The reaction mixture was then diluted with CH2Cl2 (5 mL), and silica was added followed by the removal of the solvent under reduced pressure. The resulting dry loaded material was purified by silica gel column chromatography eluting with hexane/EtOAc (60:40 then 50:50) to furnish II as a colourless oil (355 mg, 91%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19].N1C=CC=CC=1>C1C=CC=CC=1>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.7 %

Procedure:
Benzoyl chloride (140.5 g., 1.0 mole) was added dropwise with stirring to a solution of p-chloro-m-(trifluoromethyl)aniline (181.5 g., 1.0 mole) and pyridine (79 g., 1.0 mole) in two liters of dry benzene. Although the reaction was heated initially, the addition of benzoyl chloride generated sufficient heat to maintain reflux conditions during the addition. The reaction mixture was stirred overnight at room temperature and then was heated under reflux for 2 hours. After being cooled to about 25° C., the reaction product was washed successively with 6 N hydrochloric acid and saturated aqueous sodium bicarbonate solution, was dried over magnesium sulfate and was filtered. The filtrate was evaporated by distillation in vacuo, and the residue was crystallized from a benzene-hexane solvent to give two grams of 4'-chloro-3'-(trifluoromethyl)benzanilide, having a melting point of 130°-131° C.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[F:33][C:34]([F:49])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:35][CH2:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:15](=[O:16])[C@H:14]([N:5]2[CH2:6][C@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C@@H:3]([CH2:1][N:40]3[CH2:41][CH2:42][CH:37]([CH2:36][CH2:35][C:34]([F:33])([F:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:38][CH2:39]3)[CH2:4]2)[CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:20][CH:21]=1
Reactant: FC(F)(CCC1CCNCC1)c1ccccc1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(CCC(F)(F)c4ccccc4)CC3)[C@@H](c3ccccc3)C2)cc1
Reaction time: 4 h
Yield: 66.2 %

Procedure:
Molecular sieve pellets (3 A) were added to a solution of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid (4-methoxy)benzyl ester (34 mg, 0.078 mmol, from EXAMPLE 33, Step E) and 4-(3,3-difluoro-3-phenylpropyl)piperidine (20 mg. 0.084 mmol, from EXAMPLE 154, Step D) in 1,2-dichloroethane (0.75 mL). The mixture was stirred for 45 min. at RT before the addition of sodium triacetoxyborohydride (19.9 mg, 0.094 mmol). After 4 h, the mixture was diluted with EtOAc (20 mL) and washed with saturated aq. NaHCO3 (10 mL) followed by saturated aq. NaCl (10 mL). The organic layer was dried (Na2SO4), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 92:8 v/v, then 86:14 v/v hexanes/EtOAc, gave 34 mg of the title compound as a colorless film. 1H NMR (400 MHz, CD3OD) δ 7.47-7.40 (m, 5H), 7.36 (d, J=8,22H), 7.23 (t, J=7, 2H), 7.15 (t, J=7, 1H), 7.10 (d, J=7, 1H), 6.90 (d, J=8, 2H), 5.12 (s, 2H), 3.18 (dd, J=9, 7, 1H), 3.12-3.06 (m, 2H), 2.80-2.56 (m, 4H), 2.51 (dd, J=9, 7, 11H), 2.30-2.19 (m, 3H), 2.12 (tm, J=16, 2H), 1.94 (bd, J=12, 1H), 1.86-1.50 (m, 9H), 1.31-0.89 (m, 10H); ESI-MS 659 (M+H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].Cl[C:33]1[CH:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1>>[F:31][C:2]([F:30])([F:1])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][N:27]([C:33]3[CH:42]=[C:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6]
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Reactant: O=C(NCC(F)(F)F)C1(CCCCN2CCNCC2)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cc(-c4ccccc4)c4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 21 from 9-(4-piperazin-1-yl-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-chloro-4-phenyl-quinoline.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37])[C:8]([O:10]C(C)(C)C)=[O:9])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:28]1(=[O:37])[N:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:7]([C:6]([OH:38])=[O:5])[C:8]([OH:10])=[O:9])[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]12
Reactant: CC(C)(C)OC(=O)C(CCCCCCCCCCCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(CCCCCCCCCCCCN1C(=O)c2ccccc2C1=O)C(=O)O
Yield: 100 %

Procedure:
Following general procedure D, 16.0 mmol (8.45 g) of 5c and 160 mmol (11.9 mL) of trifluoroacetic acid were reacted in 12 mL of dichloromethane at room temperature and the mixture was processed. Yield 100%.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[S:16][C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.[CH3:32][O:33][C:34]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:35]=1[C:36](O)=[O:37].F[B-](F)(F)F.C(OC(C(=NOC(N(C)C)=[N+](C)C)C#N)=O)C>CN(C)C=O>[CH:20]([C:17]1[S:16][C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][NH:2][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:41]([C:43]([F:45])([F:46])[F:44])=[CH:42][C:34]=3[O:33][CH3:32])=[CH:6][CH:7]=2)(=[O:13])=[O:12])=[N:19][N:18]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1nnc(NS(=O)(=O)c2ccc(CCN)cc2)s1
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)ccc1C(=O)NCCc1ccc(S(=O)(=O)Nc2nnc(C(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
6.53 g 4-(2-Amino-ethyl)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzene sulfonamide hydrochloride were dissolved in 150 ml dimethylformamide. 8.54 ml N,N-diisopropylethylamine, 3.6 g 2-methoxy-4-(trifluoromethyl)benzoic acid and 6.44 g O-((Ethoxycarbonyl)cyanomethyleneamino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the resulting residue was purified by RP-HPLC to obtain 5.0 g N-{2-[4-(5-Isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl]-ethyl}-2-methoxy-4-trifluoromethyl-benzamide as white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[OH-].[Na+].OO.CC[O:17]CC>C1COCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH2:3][OH:17])=[CH:5][CH:6]=1
Reactant: CCOCC
Reactant: C=CCc1ccc(Br)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
BH3 (1M in THF, 412 mL, 412 mmol) is added to a sol. of 1-allyl-4-bromo-benzene (204 g, 1.03 mmol) in THF (1.00 L) under nitrogen at 0° C. The mixture is stirred overnight while warming up to rt. Aq. NaOH (2.5M, 1.65 L, 4.12 mol) is added, and the mixture is cooled to 0° C. H2O2 (35%, 480 mL, 5.15 mol) is dropped carefully, and the mixture is stirred for 3 h. Et2O is added, and the phases are separated. The org. layer is washed with water (1×), and brine (1×). The org. layer is dried over MgSO4, filtered, and the solvents are removed under reduced pressure. Purification by FC (Et2O/petroleum ether 1:1→Et2O) yields the title compound (97.4 g, 44%).
Reaction SMILES: [CH:1]([CH:3]([Br:6])[CH:4]=O)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1.C(O)(=O)C>C(O)C>[Br:6][C:3]1[CH:1]=[N:15][C:11]2[C:12]([CH:4]=1)=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[CH:10]=2
Reactant: COc1cccc(N)c1
Reactant: O=CC(Br)C=O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2cc(Br)cnc2c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 20 %

Procedure:
For the synthesis of this starting compound, 1.80 g (12.3 mmol, 1.1 eq) of bromomalondialdehyde was first dissolved in 30 ml of ethanol, and 1.25 ml of m-anisidine was added. This reaction mixture is stirred over night at RT and, after the addition of acetic acid (20 ml), at 100° C. for 10 days. The solvent is subsequently removed in vacuum on a rotary evaporator, and the residual solid is partitioned between a water and an ethyl acetate phase. The aqueous phase is made alkaline with an ammonia solution, and insoluble particles were filtered off. The filtrate is extracted with ethyl acetate, and the organic phase is dried over MgSO4, filtered, and the solvent is removed in vacuum on a rotary evaporator. The product was purified by column chromatography with a mixture of hexane/ethyl acetate 8/2 as the eluent in a yield of 20% (700 mg).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].Cl.[N:15]1([C:20]([NH2:22])=[NH:21])[CH:19]=[CH:18][CH:17]=N1>C(#N)C.O>[ClH:1].[ClH:1].[NH:11]([CH2:10][CH2:9][C:8]1[CH:12]=[CH:13][C:5]([NH2:2])=[CH:6][CH:7]=1)[C:20]([NH2:21])=[NH:15].[N+:2]([C:5]1[CH:13]=[CH:12][C:17]([CH2:18][CH2:19][NH:15][C:20]([NH2:22])=[NH:21])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: N=C(N)n1cccn1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: N=C(N)NCCc1ccc(N)cc1
Product: N=C(N)NCCc1ccc([N+](=O)[O-])cc1

Procedure:
4-(2-Guanidinoethyl)aniline dihydrochloride was prepared as follows. 4--Nitrophenethylamine hydrochloride (1.013 g, 5 mmol), 1H-pyrazole-1-carboxamidine hydrochloride (0.733 g, 5 mmol) and N-diisopropylethylamine (0.88 ml, 5 mmol) in acetonitrile (10 ml) and water (10 ml) were stirred at ambient temperature for 16 hours. Preparative RP-HPLC was carried out in two portions using a Dynamax 60A, C18 column (one inch internal diameter) eluting with acetonitrile and water containing 0.1% TFA to afford pure 4-nitrophenethylguanidine. The product was dissolved in water (10 ml) and one drop of concentrated hydrochloric acid was added, followed by 5% palladium on carbon (100 mg) and hydrogen was bubbled through the solution for 4 hours. The catalyst was removed by filtration and washed with water. Volatile material was removed by evaporation to give 4-(2-guanidinoethyl)aniline dihydrochloride as a brown foam (0.984 g) (after drying over potassium hydroxide pellets).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](O)=[O:17])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[CH3:19])(=[O:3])[CH3:2].[CH3:20][N:21]([CH3:36])[CH2:22][CH2:23][O:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][C:26]=1[O:34][CH3:35]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([N:31]3[C:32]4[C:28](=[CH:27][C:26]([O:34][CH3:35])=[C:25]([O:24][CH2:23][CH2:22][N:21]([CH3:20])[CH3:36])[CH:33]=4)[CH:29]=[CH:30]3)=[O:17])=[CH:14][CH:15]=2)=[CH:6][C:5]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1C
Reactant: COc1cc2cc[nH]c2cc1OCCN(C)C
Product: COc1cc2ccn(C(=O)c3ccc(-c4ccc(C(C)=O)c(C)c4)cc3)c2cc1OCCN(C)C

Procedure:
The title compound was prepared from 4'-acetyl-3'-methylbiphenyl-4-carboxylic acid (D21) and 6-(2-dimethylaminoethoxy)-5-methoxy-1H-indole (D13) using a similar procedure to Example 4 as an off-white solid mp 125°-127° C. (36%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1>C(#N)CCC>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[CH2:13][CH2:12][CH2:18][S:15]([OH:17])(=[O:16])=[O:14]
Reactant: Oc1cccc2c1CCCN2
Reactant: O=S1(=O)CCCO1
Solvent: CCCC#N
Product: O=S(=O)(O)CCCN1CCCc2c(O)cccc21
Temperature: 125 °C

Procedure:
A mixture of 0.8 g (5.36 mmol) of 5-hydroxy-1,2,3,4-tetrahydroquinoline and 0.5 g 1,3-propanesultone (4.1 mmol) in 12 ml of butyronitrile was heated at 125° C. for hours. The mixture was suction filtered and the filtrate evaporated under reduced pressure. The resulting off white compound crystallized. Product washed with ethyl ether and filtered of. Yield 0.8 g (80%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17](Cl)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([S:27]([F:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([NH:20][C:21]3[CH:22]=[C:23]([S:27]([F:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=3)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Reactant: Nc1cccc(S(=O)(=O)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc(S(=O)(=O)F)c1)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (3.00 g, 9.70 mmol) was added to 3-amino-benzenesulfonyl fluoride (1.87 g, 10.6 mmol) in CH2Cl2 (50 ml) containing pyridine (2.35 ml, 29.1 mmol). Reaction mixture stirred overnight at room temperature, concentrated under reduced pressure and crude product purified by column chromatography to give 3-{[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-benzenesulfonyl fluoride (3.23 g, 74%).