Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[C:4]([O:30][CH3:31])[CH:3]=1.Cl[CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:19]=[C:20]([CH:24]5[CH2:25][CH2:26][N:27]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:28][CH2:29]5)[CH:21]=[CH:22][CH:23]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[C:4]([O:30][CH3:31])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-c1cccn2nc(Nc3cccc(C4CCNCC4)c3)nc12
Reactant: CN(C)C(=O)CCl
Product: COc1cc(Cl)ccc1-c1cccn2nc(Nc3cccc(C4CCN(CC(=O)N(C)C)CC4)c3)nc12

Procedure:
2-(4-{3-[8-(4-Chloro-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(4-chloro-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(3-piperidin-4-yl-phenyl)-amine (0.047 g, 0.110 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.017 mL, 0.160 mmol) in a manner analogous to Example 313 to give product (0.012 g, 21%). MP=79-82° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.59 (s, 1H), 8.77 (d, 1H), 7.60 (m, 3H), 7.45 (d, 1H), 7.25 (s, 1H), 7.15 (m, 2H), 7.05 (m, 1H), 6.75 (d, 1H), 3.78 (s, 3H), 3.15 (s, 2H), 3.05 (s, 3H), 2.95 (m, 2H), 2.80 (s, 3H), 2.35 (m, 1H), 2.15 (m, 2H), 1.65 (m, 4H): MS=520 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+4].[O-2]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][C:10]=1[S:17]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1cc(CO)ccc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(OCc2ccccc2)c(S(=O)(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.1 g (5.64 mmol) of {4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]phenyl}methanol (Example V) are dissolved in 25 ml of dichloromethane. At room temperature, 4.9 g (56.39 mmol) of manganese(IV) oxide are added. The mixture is stirred at room temperature overnight. The reaction mixture is then filtered through Celite and the solvent is removed under reduced pressure. This gives 1.82 g (86% of theory) of 4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]benzaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([S:15][C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH3:26])[CH:6]=1)[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=[C:7]([S:15][C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[C:17]=2[CH3:26])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Sc2c(C)[nH]c3cc(Cl)ccc23)cc(C(F)(F)F)c1
Reactant: Brc1cccnc1
Product: CCOC(=O)c1cc(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-5-trifluoromethyl-benzoic acid ethyl ester and 3-bromopyridine.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]([CH3:19])[C:17](=[O:20])[C:16]3[C:11](=[C:12]([CH3:21])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.B(F)(F)F.[OH-].[Na+]>ClCCl.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:18]([CH3:19])[C:17](=[O:20])[C:16]3[C:11](=[C:12]([CH3:21])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3c(C)cccc3c(=O)n2C)cc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cccc2c(=O)n(C)c(-c3ccc(O)cc3)nc12
Temperature: -78 °C
Yield: 80.3 %

Procedure:
2-(4-Methoxyphenyl)-3,8-dimethyl-4(3H)-quinazolinone (2.02 g, 7.20 mmol) was dissolved in dichloromethane (10 ml), stirred at −78° C., then boron trifluoride (1.0 M in CH2 Cl2, 21.6 ml) was added thereto, gradually heated up to room temperature, and stirred at that temperature for 12 hours. The reaction solution was diluted with ethyl acetate, and with cooling with ice, this was poured into aqueous 1 N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and saturated saline water, and dried with magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain the intended compound (1.54 g, 80%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.F[C:10]1[N:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]>>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([O:1][C:10]2[N:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:3][CH:4]=1
Reactant: N#Cc1cccnc1F
Reactant: Cc1ccc(O)cn1
Product: Cc1ccc(Oc2ncccc2C#N)cn1

Procedure:
5-hydroxy-2-methylpyridine and 2-fluoronicotinonitrile were processed according to the method of Example 128B to provide the product. MS (ESI+) m/z 212 (M+H)+;
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25]>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][S:24]([N:23]([CH3:28])[CH3:22])(=[O:26])=[O:25])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Product: CN(C)S(=O)(=O)Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Yield: 37.4 %

Procedure:
Prepared from N2-(3-cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (200 mg, 0.72 mmol) and dimethylsulfamoyl chloride (122 mg, 0.85 mmol) according to the procedure described for example 27. Obtained the title compound as an off-white foam (104 mg, 37%), MS (ISP) m/e=385.3 [(M−H)+].
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:11]([OH:13])=O)[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:64])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:35][CH:34]=1>CN(C=O)C>[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:64][C:11](=[O:13])[C@H:7]([CH:8]([CH3:9])[CH3:10])[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:37][CH:38]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1)C(C)C
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C

Procedure:
Analogously to Example 7, 106 mg (0.56 mmol) of N-ethoxycarbonyl-(L)-valine, 201 mg (1.05 mmol) of EDC and 95 mg (0.7 mmol) of HOBT in 4.6 ml of DMF and 293 μl (2.1 mmol) of TEA are reacted with 0.35 mmol of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane to form the title compound: Anal. (C35H48N6O7S (0.20 H2O)) calc. C 60.01, H 6.96, N 12.00, S 4.58, H2O 0.51: found C 60.07, H 6.78, N 11.93, S 4.70, H2O 0.52; HPLC20-100 : tRet =14.6; FAB MS (M+H)+ =697.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[Na+].[C:29]([CH2:32][S:33][C:34]1[S:35][C:36]([SH:39])=[N:37][N:38]=1)(=[NH:31])[NH2:30]>CN(C=O)C>[C:29]([CH2:32][S:33][C:34]1[S:35][C:36]([S:39][CH2:18][C:15]2[CH2:16][S:17][C@@H:12]3[C@H:11]([NH:10][C:8](=[O:9])/[C:7](/[C:4]4[N:3]=[C:2]([NH2:1])[S:6][N:5]=4)=[N:25]\[O:26][CH3:27])[C:23](=[O:24])[N:13]3[C:14]=2[C:20]([OH:22])=[O:21])=[N:37][N:38]=1)(=[NH:30])[NH2:31]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1nsc(N)n1
Reactant: N=C(N)CSc1nnc(S)s1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnc(SCC(=N)N)s3)CS[C@H]12)c1nsc(N)n1
Temperature: -20 °C
Yield: 74.4 %

Procedure:
To a solution of 371 mg of sodium 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4-carboxylate and 309 mg of 2-amidinomethylthio-5-mercapto-1,3,4-thiadiazole in 10 ml of DMF was added 600 mg of ethyl o-phenylenephosphate under stirring at -20° C. After stirring at -20° C. to 0° C. for 60 minutes, the mixture was subjected to a column chromatography on silica gel (100 g), being washed with acetonitrile and eluted with acetonitrile/water (4:1). The eluate was concentrated under reduced pressure, and the resultant solid was dissolved in dilute hydrochloric acid. This aqueous solution was subjected to a column chromatography on XAD-II (150 ml), being washed with water and eluted with 30% aqueous ethanol. The eluate was concentrated under reduced pressure and lyophilized to give 381 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1C1(C=CC=CC1)CO.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl>>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:27](=[O:33])[O:26][CH:24]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C1(CO)C=CC=CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C(c2ccccc2)O1

Procedure:
Prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-benzyl alcohol and triphosgene according to the procedure of Example 9. Off-white solid: mp 177-178° C.; 1H-NMR (DMSO-d6) δ 10.5 (s, 1H), 7.68 (dd, 1H, J=8.7, 1.7 Hz), 7.62 (t, 1H, 1H, J=1.74 Hz), 7.54-7.5 (m, 1H), 7.48-7.34 (m, 8H), 7.04 (d, 1H, J=8.7 Hz), 1H) MS (ESI) m/z 336 ([M+H]+, 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2.[CH3:18][C:19]1(OC)[CH2:23][CH2:22][C:21]([CH3:26])(OC)O1>>[CH3:18][C:19]1[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]3)[C:21]([CH3:26])=[CH:22][CH:23]=1
Reactant: COC1(C)CCC(C)(OC)O1
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1C(F)(F)F
Product: Cc1ccc(C)n1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1C(F)(F)F

Procedure:
12.2 mmol of 6-amino-7-trifluoromethyl-2,3(1H,4H)-quinoxalinedione were reacted with 12.2 mmol of 2,5-dimethyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.CCN=C=NCCCN(C)C.[CH2:33]([CH2:35][NH2:36])[OH:34]>CN(C=O)C.ClCCl>[Cl:21][C:10]1[CH:9]=[C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)[C:13]([C:14]([NH:36][CH2:35][CH2:33][OH:34])=[O:16])=[CH:12][C:11]=1[S:17](=[O:19])(=[O:18])[NH2:20]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)NCCO)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
To furosemide (1.013 g, 3.0627 mmol) in DMF (3 mL) was added EDAC (608.3 mg, 3.173 mmol) in dichloromethane (3 mL) and then ethanolamine (185 μL, 3.065 mmol). The reaction solution was stirred at ambient temperature for 3 hours, and concentrated to dryness under high vacuum. The crude product was treated with water, and the resultant gum collected and chromatographed on silica gel eluting with methanol:dichloromethane (1:20) to give the title compound (476 mg, 42% yield). Mp 183-185° C. 1H NMR (300 MHz, CD3OD) δ8.17 (s, 1H), 7.45 (m, 1H), 6.94 (s, 1H), 6.37-6.36 (m, 1 H), 6.32-6.31 (m, 1H), 4.44 (s, 2H), 3.70-3.66 (m, 2H), 3.32-3.29 (m, 2H). 13C NMR (75 MHz, CD3OD) δ 170.4, 153.0, 152.7, 143.6, 136.7, 131.3, 127.5, 114.8, 114.4, 111.4, 108.5, 61.5, 43.2, 40.7. LRMS (APIMS) m/z 374(MH+).
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)C.O.[F:19][C:20]([F:25])([F:24])[CH2:21][NH:22][NH2:23]>C(O)(=O)C.O>[F:19][C:20]([F:25])([F:24])[CH2:21][N:22]1[C:4](=[O:17])[CH2:5][C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:23]1
Reactant: NNCC(F)(F)F
Reactant: CCOC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC(c2cccc([N+](=O)[O-])c2)=NN1CC(F)(F)F

Procedure:
0.15 Mole (35.6 g) of m-nitrobenzoyl acetic acid ethyl ester and 0.15 mole (25.2 g) of 2,2,2-trifluoroethyl hydrazine hydrate were stirred together for 2 hours in 90 ml of boiling acetic acid. Subsequently, the reaction mixture was poured out in water. After stirring and filtration, the precipitate was recrystallized from methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20]1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1CCNC(=O)C1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1CCNC(=O)C1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-δ-valerolactam (prepared by the procedure of D. W. Adamson, J. Chem. Soc. 1943, 39), the title compound was prepared.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][NH:18][CH:19]([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CNC(C)C
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)C(C)C)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (3 g, 12.57 mmol) in DMSO (20 ml) was added methyl(propan-2-yl)amine (1.3 g, 17.77 mmol), and DIEA (3.2 g, 24.76 mmol). The resulting solution was stirred overnight at 70° C. The product was precipitated by the addition of ice/water and collected by filtration to afford methyl 3-[methyl(propan-2-yl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (2.5 g, 72%).
Reaction SMILES: [CH:1]#[C:2][C@@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:9][C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#C[C@@H](O)CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC[C@H](O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, (S)-(−)-1-octyn-3-ol (61 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (S)-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 101 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12]([C:21]([OH:23])=[O:22])=[CH:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[C:24](Cl)(=O)C(Cl)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12]([C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(C(=O)O)=CC[C@@H]12
Solvent: ClCCl
Product: COC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Methoxyestra-1,3,5(10),16-tetraene-17-carboxylic acid (Compound J) (2.00 g) obtained according to the method described in Tetrahedron Letters, 26: 1109 (1985) was dissolved in dichloromethane (75 mL), and oxalyl chloride (2.3 mL) was added thereto under ice-cooling, followed by stirring at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated, the residue was dissolved in dichloromethane (60 mL), and methanol (30 mL) and triethylamine (3.58 mL) were added thereto, followed by stirring at room temperature for 11.5 hours. After completion of the reaction, the reaction solution was concentrated, methanol (20 mL) and 2 mol/L hydrochloric acid (40 mL) were added to the residue, and the resulting precipitate was collected by filtration, and washed with 1 mol/L hydrochloric acid and then water, followed by drying under reduced pressure to give methyl 3-methoxyestra-1,3,5(10), 16-tetraene-17-carboxylate (2.01 g).
Reaction SMILES: [NH2:1][C:2]1[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([N:21]=[C:22]=[O:23])[CH:18]=[CH:19][CH:20]=1.O>CS(C)=O>[O:12]=[C:8]1[NH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:22]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:24])[F:25])[CH:16]=2)=[O:23])[C:10](=[O:11])[NH:9]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1c(C(=O)O)[nH]c(=O)[nH]c1=O
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1c(C(=O)O)[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Amino-orotic acid (0.86 g) was dissolved in DMSO (10 ml), treated with 3-trifluoromethylphenylisocyanate (0.9 ml) and after an hour with another 0.5 ml. The reaction was stirred for three days at room temperature. Water was added and the mixture was filtered and washed with water. The residue was slurried in water, treated with NaOH and worked through until basic. Filtration and acidification of the filtrate provided a precipitate, which was filtered, washed with water and dried. Recrystallisation from 96% EtOH provided 2,6-dioxo-5-[3-(3-trifluoromethyl-phenyl)-ureido]-1,2,3,6-tetrahydro-pyrimidine-4-carboxylic acid (330 mg). Mp. >300° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH2:13]([NH2:16])[CH2:14][CH3:15].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1.C1COCC1.O>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:16][CH2:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: CCCN
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCNC(=O)Nc1cccc(N)c1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with N-3-aminophenyl-N'-propylurea to generate the title compound. The N-3-aminophenyl-N'-propylurea was prepared by sequentially treating commercial 3-nitrophenylisocyanate with PrNH2 in THF at 20° C. followed by reduction with Na2S2O4 in THF/H2O at 100° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[N:25]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][N:25]=2)=[O:34])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1n[nH]c2ccccc12
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2n[nH]c3ccccc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1H-Indazole-3-carboxylic acid. LC-MS (basic): tR=0.87 min; [M+H]+=492.3.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].[Br:14]Br>ClCCl>[Br:14][C:11]1[CH:12]=[CH:13][C:6]([CH3:5])=[C:7]([CH:10]=1)[CH:8]=[O:9]
Reactant: BrBr
Reactant: Cc1ccccc1C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(Br)cc1C=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
77.7 g (583 mmol) of aluminium trichloride are suspended in 200 ml of dichloromethane and cooled to 0° C. 40.0 g (333 mmol) of 2-methylbenzaldehyde are added dropwise over the course of 30 min. Then 53.2 g (333 mmol) of bromine are added at 0° C. over the course of 6 h, and the mixture is allowed to warm to RT and is stirred for 12 h. The reaction solution is added to 500 ml of ice-water. The aqueous phase is extracted several times with dichloromethane. The combined organic phases are washed successively with 2N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. Purification is by silica gel chromatography and subsequently by crystallization from cyclohexane. The precipitated product is filtered off.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]1[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[NH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])C.[OH-].[Na+]>CCO>[C:21]1([CH:11]([C:12]2[C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:15]=3[NH:14][CH:13]=2)[CH:5]([C:4]([OH:27])=[O:3])[C:6]([OH:8])=[O:7])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1c[nH]c2ccncc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(C(=O)O)C(c1ccccc1)c1c[nH]c2ccncc12
Temperature: 25 °C
Yield: 52.3 %

Procedure:
To a RT solution of 2-[phenyl-(1H-pyrrolo[3,2-c]pyridin-3-yl)-methyl]-malonic acid diethyl ester (0.77 g) in EtOH (40 mL) was added NaOH (2 M in water, 15 ml). The mixture was stirred at reflux for 5 h, cooled to RT, and concentrated. The aqueous residue was acidified by addition of HCl (1 M) until dissolution. To this solution was added EtOAc resulting in precipitation of a solid, which was collected by filtration and dried, affording 2-[Phenyl-(1H-pyrrolo[3,2-c]pyridin-3-yl)-methyl]-malonic acid (341 mg, 52% yield).