Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)=[N:6][CH:5]=1.O.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C.C(OC)(OC)OC.[Pd]>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[N:10]=[CH:30][N:13]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)[C:7]2=[N:6][CH:5]=1)=[O:28]
Reactant: COC(=O)c1cnc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Pd]
Solvent: COC(OC)OC
Solvent: O
Solvent: CO
Product: COC(=O)c1cnc2c(c1)ncn2-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of XXIV (235 mg, 0.62 mmol) in MeOH (3 mL) and ethyl acetate (3 mL) was added 10% Pd—C (47 mg) under nitrogen atmosphere. The resulting mixture was hydrogenated at rt overnight. The catalyst was removed by filtration under nitrogen and washed with methanol, the filtrate was concentrated under reduced pressure to give a white solid. MS (ES, Pos.): m/z 260 [MH+]. The hydrogenation product was suspended in trimethyl orthoformate (5 mL), and p-toluenesulfonic acid monohydrate (12 mg, 0.062 mmol) was added. The resulting mixture was stirred at rt overnight. The white solid was collected by filtration. MS (ES, Pos.): m/z 270 [MH+]. 1H NMR (CD3OD, 400 MHz): δ=3.99 (s, 3H), 7.00 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 8.71 (d, J=1.8 Hz, 1H), 8.72 (s, 1H), 9.05 (d, J=1.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[N:23][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(N2CCC(O)C2)nc1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: O=C(c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(O)C2)nc1)C1CC1
Yield: 51.6 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 1-(5-aminopyridin-2-yl)pyrrolidin-3-ol (269 mg, 1.5 mmol) to afford the desired product (234 mg, 51%) as a yellow solid: ESI MS m/z 453 [C22H21BrN4O2+H]+.
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[C:2]=[O:3].[N:14]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[NH:17][CH2:16][CH2:15]2>>[C:4]1([NH:1][C:2]([N:17]2[CH:18]3[CH2:21][CH2:22][N:14]([CH2:20][CH2:19]3)[CH2:15][CH2:16]2)=[O:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: C1CN2CCC(CC2)N1
Product: O=C(Nc1cccc2ccccc12)N1CCN2CCC1CC2
Yield: 48 %

Procedure:
Using general procedure A, 1-isocyanatonaphthalene (208 mg, 1.23 mmol) and 1,4-diazabicyclo[3.2.2]nonane gave the title compound as a white solid (150 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 7.80-7.72 (m, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.44-7.35 (m, 3H), 6.65 (br s, 1H), 4.18 (br s, 1H), 3.64 (t, J=8.0 Hz, 2H), 3.09-2.91 (m, 6H), 2.08-1.93 (m, 2H) 1.74-1.66 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3) δ 155.3, 134.4, 134.3, 128.9, 128.2, 126.2, 126.1, 126.0, 125.1, 121.2, 121.0, 57.6, 48.7, 46.4, 46.4, 42.2, 27.6, 27.6 ppm. Purity: >99% UPLCMS (210 nm); retention time 0.53 min; (M+1) 296.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([O:15][C:16]1[CH:33]=[CH:32][C:31]2[C@@H:30]3[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]3)([CH3:27])[C:25]([C:35]([F:38])([F:37])[F:36])([OH:34])[CH2:24][CH:23]4[CH2:39][CH2:40][CH2:41][CH2:42][OH:43])[CH2:20][CH2:19][C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([O:15][C:16]1[CH:33]=[CH:32][C:31]2[C@@H:30]3[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]3)([CH3:27])[C:25]([OH:34])([C:35]([F:38])([F:36])[F:37])[CH2:24][CH:23]4[CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:20][CH2:19][C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C(CCCCO)CC2(O)C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCCCCC1CC(O)(C(F)(F)F)[C@@]2(C)CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
Pivaloylchloride (0.50 ml; 4.10 mmol) was added dropwise to a solution of 3-Benzyloxy-15-(4-hydroxybutyl)-17-trifluoromethyl-estra-1,3,5(10)-trien-17-ol (1.65 g; 3.28 mmol) in pyridine (15 ml) at 0° C. After stirring for 2 h, the reaction mixture was poured into ice water and stirred for another h. After extraction with DCM, the combined organic phases were dried over MgSO4. After evaporation of the solvent, the residue was purified by column chromatography (SiO2, DCM) yielding the title compound (1.85 g, 96%) as colourless oil.
Reaction SMILES: Cl.[CH:2](=[C:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:3]1[CH:8]=CC=CC=1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C=C.C([Li])CCC.[CH2:43](N1CCC(=O)CC1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH2:43]([N:12]1[CH2:11][CH2:10][C:9](=[CH:2][CH2:3][CH3:8])[CH2:14][CH2:13]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C(=C1CCNCC1)c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: C=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Synthesis of 4-propenylidenepiperidine hydrochloride (1) In a stream of argon, 2.9 g (7.5 mmol) of allyltriphenylphosphonium bromide was suspended in 10 ml of anhydrous tetrahydrofurane, and thereto 4.3 ml of butyllithium was added dropwise under cooling with ice. After stirring the mixture at room temperature for 30 minutes, thereto was added dropwise a solution of 1 g (5.3 mmol) of 1-benzyl-4-piperidone in anhydrous tetrahydrofurane under cooling with ice and the obtained mixture was stirred at room temperature for 15 hours. The reaction solution was filtrated, and ethyl acetate and water were added to the filtrate, and the organic phase was taken out. The organic phase was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting oily matter was subjected to a column chromatography using 40 g of silica gel and eluted with ethyl acetate-hexane (1:1 to 1:3 ) to obtain 200 mg of 1-benzyl-4-propylidenepiperidine.
Reaction SMILES: [C:1]([NH:6][C:7](=[O:11])OCC)(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:1]([NH:6][C:7]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)NC(=O)OCC
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)NC(=O)Nc1ccccc1
Temperature: 120 °C
Yield: 45.5 %

Procedure:
A reaction vessel was charged with 78.5 g of ethyl N-methacryloylcarbamate and 46.5 g of aniline to which 100 g of toluene were added and heated at 120° C. for 30 minutes. The resulting mixture was condensed under reduced pressure and isolated by column chromatography to obtain 46.4 g of N-methacryloyl-N'-phenyl urea having a melting point of 165° to 166° C.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1>>[F:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][C:23]=2[C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3-c3cccnc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-Bromo-4-trifluoromethyl-phenoxy)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with pyridine-3-boronic acid as in Example 38 to afford 0.115 g (66%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H21NO4F4 511, found 512 (M+1, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[C:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])[CH3:13]>CCOC(C)=O.O>[C:12]([N:15]1[CH2:20][CH2:19][N:18]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[Cl:1])[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C

Procedure:
2-Chloro-1-fluoro-4-nitrobenzene (10 g, 57 mmol) and 1-acetylpiperazine (14.6 g, 114 mmol) were heated neat at 55° C. for 1 h. Then the reaction mixture was allowed to cool down to room temperature. The viscous orange solution was diluted with EtOAc and water. The organics were washed with water (3 times), brine, dried and evaporation of the solvent gave an orange oil which was triturated with isohexane. After evaporation of solvent the title compound was obtained as a yellow solid which was dried overnight in vac oven at 50° C. (15.68 g, 97%). It was used without further purification. NMR (400 MHz) 2.03 (d, 3H), 3.18 (dt, 4H), 3.62 (m, 4H), 7.30 (d, 1H), 8.17 (dd, 1H), 8.26 (d, 1H); m/z 284-286.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([OH:3])=[O:2].[NH2:12][C:13]1[C:18]([NH2:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(OCC)(=O)C.C(OCC)C>[N+](C1C=CC=CC=1)([O-])=O>[N+:20]([C:16]1[CH:17]=[C:18]2[N:19]=[C:7]([C:6]3[CH:5]=[C:4]([CH:11]=[CH:10][CH:9]=3)[C:1]([OH:3])=[O:2])[NH:12][C:13]2=[N:14][CH:15]=1)([O-:22])=[O:21]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1cccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)c1
Temperature: 25 °C

Procedure:
0.87 g 3-carboxybenzaldehyde and 0.866 g 2,3-diamino-5-nitropyridine in 50 ml nitrobenzene were heated to 160° C. for 30 hrs. The mixture was cooled to room temperature and 200 ml ethyl acetate and 100 ml ethyl ether were added. The precipitated product was collected by filtration and dried. Yield 1.135 g
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:31][O:32]C1C=CC(N=C=O)=CC=1>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][C:25]([O:32][CH3:31])=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Product: COc1ccc(N2CCN(CCN3CCC(c4noc5cc(F)ccc45)CC3)C2=O)cc1

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 4-methoxyphenyl isocyanate in Step 1 of the synthesis. The expected product melts at 154°-157° C.
Reaction SMILES: CN1CCOCC1.[CH3:8][O:9][C:10](=[O:61])[NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]1[NH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[NH:41][C:42]([CH:45]5[CH2:49][NH:48][CH2:47][N:46]5[C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])=[N:43][CH:44]=4)=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:26][N:27]=1)=[O:17])[CH:13]([CH3:15])[CH3:14].Cl[C:63]([O:65][CH3:66])=[O:64]>ClCCl>[CH3:66][O:65][C:63]([N:48]1[CH2:49][CH:45]([C:42]2[NH:41][C:40]([C:37]3[CH:36]=[CH:35][C:34]([C:31]4[CH:32]=[CH:33][C:28]([C:25]5[NH:24][C:23]([CH:19]6[CH2:20][CH2:21][CH2:22][N:18]6[C:16](=[O:17])[CH:12]([NH:11][C:10]([O:9][CH3:8])=[O:61])[CH:13]([CH3:15])[CH3:14])=[N:27][CH:26]=5)=[CH:29][CH:30]=4)=[CH:39][CH:38]=3)=[CH:44][N:43]=2)[N:46]([C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[CH2:47]1)=[O:64]
Reactant: COC(=O)Cl
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CNCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(C(=O)OC)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Yield: 16.8 %

Procedure:
4-Methylmorpholine (31 μL, 0.28 mmol) was added to a suspension of {1-[2-(5-{4′-[3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-3H,1′H-[2,4]biimidazolyl-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (41.1 mg, 0.056 mmol) [prepared via reaction of 3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester with HCl-solution] in dichloromethane (5 mL). Methyl chloroformate (16.5 μL, 0.21 mmol) was added to the resulting solution. After 20 minutes the solvent was removed in vacuo. The residue was taken into tetrahydrofuran (4 mL) and methanol (2 mL) and an aqueous solution of sodium hydroxide (2 N, 1 mL) was added. After 2 hours the organic solvents were removed in vacuo and the aqueous phase was decanted. The residue was dissolved in dimethylformamide (2 mL) and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA). The product-containing fractions were combined and the solvent was removed by lyophilization to provide 3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid methyl ester (7.5 mg) C41H51N9O8 calculated 797.4 observed [M+1]+ 798.4; 1H (DMSO-d6): δ=8.08 (s, 1H), 7.83 (m, 8H), 7.58 (d, J=8.0 Hz, 1H), 7.29 (s, J=8.4 Hz, 1H), 5.42 (dd, J=7.6, 3.6 Hz, 1H), 5.26 (d, J=4.8 Hz, 1H), 5.18 (d, J=6.0 Hz, 1H), 5.10 (t, J=7.2 Hz, 1H), 4.88 (m, 1H), 4.08 (t, J=7.6 Hz, 2H), 3.94 (m, 1H), 3.82 (m, 4H), 3.65 (s, 3H), 3.52 (s, 3H), 3.51 (s, 3H), 2.36 (m, 1H), 2.01 (m, 5H), 0.83 (m, 12H).
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH:11]1[O:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12]1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:38])[CH2:36]Br)=[CH:31][C:30]=1[S:39]([NH2:42])(=[O:41])=[O:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(C(C)=O)C>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:38])[CH2:36][N:8]([CH:9]([CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[CH3:10])[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:31][C:30]=1[S:39]([NH2:42])(=[O:41])=[O:40])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: CC(NCc1ccccc1)C1COc2ccccc2O1
Solvent: CCC(C)=O
Product: CC(C1COc2ccccc2O1)N(CC(=O)c1ccc(OCc2ccccc2)c(S(N)(=O)=O)c1)Cc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 10.76 g (0.04 mole) of N-benzyl-1-(1,4-benzodioxan-2-yl)ethylamine (i1 '), 7.68 g (0.02 mole) of 2-benzyloxy-5-bromoacetylbenzenesulfonamide, and 50 ml of methyl ethyl ketone was reluxed for 2 hours with stirring and then methyl ethyl ketone was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted using a mixture of chloroform and ethyl acetate of 2:1 by volume ratio to provide 9.6 g of the isomer (i1 ') of crude 2-benzyloxy-5-[N-benzyl-1-(1,4-benzodioxan-2-yl)ethylaminoacetyl]benzenesulfonamide.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(Br)C1C=CC=CC=1.[Mg].C(OCC)(=O)C(OCC)=O>>[C:3]1([CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Agent: BrCc1ccccc1
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1ccccc1
Yield: 80 %

Procedure:
The title compound was prepared as described for B4 using benzyl bromide (1.250 g, 7.31 mmol), magnesium (0.195 g, 8.04 mmol) and diethyl oxalate (2.136 g, 14.62 mmol) in the form of colorless oil in 80% yield and used instantly in next step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]1([C:36](O)=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][N:27]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1nccc2ccccc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4nccc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and isoquinoline-1-carboxylic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=5:5:1) to yield the title compound.
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[CH2:13][CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:21][C:16]([CH2:12][CH2:13][CH:14]2[CH2:15][O:9]2)=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: c1ccc(-c2ccc(CCC3CO3)cc2)cc1
Yield: 70.87 %

Procedure:
To a stirred mixture of 88 parts of 3-chlorobenzeneperoxoic acid and 650 parts of dichloromethane are added dropwise 60 parts of 4-(3-butenyl)-1,1'-biphenyl. Upon completion, stirring is continued over week-end at room temperature. Then there are added dropwise 50 parts of a potassium carbonate solution. The organic phase is separated, washed with a sodium bisulfite solution and with water, dried, filtered and evaporated, yielding 63.5 parts (70.87%) of [2-([1,1'-biphenyl]-4-yl)ethyl]oxirane as an oily residue.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1CC[CH2:5][N:4]1[CH2:8][C:9]1[S:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:31][CH2:30][N:29]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH2:28][CH2:27]2)[CH:10]=1.[NH:38]1CCC[C@@H]1CO>>[NH2:38][C:2](=[O:1])[CH2:3][N:4]([CH2:8][C:9]1[S:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:27][CH2:28][N:29]([S:32]([CH:35]([CH3:36])[CH3:37])(=[O:33])=[O:34])[CH2:30][CH2:31]2)[CH:10]=1)[CH3:5]
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5CO)c4)cc23)CC1
Reactant: OC[C@H]1CCCN1
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CC(N)=O)c4)cc23)CC1
Yield: 53.2 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide, substituting N2-methylglycinamide (90.13 mg, 1.200 mmol) for (2R)-2-pyrrolidinylmethanol to afford 15 mg of the title compound (53.2%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:8])([O-])=O.Cl[Sn]Cl>C(O)C.C([O-])(O)=O.[Na+]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccccn1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(C(=O)Nc2ccccn2)cc1N
Reaction time: 1 h

Procedure:
A mixture of 3,4-dinitro-N-pyridin-2-yl-benzamid (725 mg, 2.5 mmol) and SnCl2×2H2O (5.7 g, 25.2 mmol) was stirred in 20 mL ethanol under argon. After stirring for 1 h the mixture was cooled and diluted with sat. NaHCO3 (aq). The aq. phase was extracted with ethyl acetate, dried over Na2SO4 and concentrated i.vac. The residue was purified by chromatography on silica gel (eluent gradient: dichloromethane/methanol=50:1->10:1)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[F:15])[CH:7]=1.[CH3:20][CH2:21]N(CC)CC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO>[F:15][C:9]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([CH:20]=[CH2:21])[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=1
Reactant: COC(=O)c1cc(Br)cc(-c2ccc(C)cc2F)c1
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCO
Product: C=Cc1cc(C(=O)OC)cc(-c2ccc(C)cc2F)c1
Temperature: 140 °C
Yield: 693.3 %

Procedure:
To Biotage Advancer MW reactor was charged methyl 5-bromo-2′-fluoro-4′-methylbiphenyl-3-carboxylate (20 g, 61.9 mmol), PdCl2(dppf) (0.20 g, 0.273 mmol), potassium vinyl trifluoroborate (12.4 g, 93 mmol), Et3N (13.0 ml, 93 mmol) and EtOH (150 ml). The reactor was sealed and heated at 140° C. for 10 min followed by flash cooling. Removed mixture from the cooling reservoir via vacuum and reaction repeated 5× (120 g, 371 mmol processed). All runs were combined and concentrated to dryness. The crude was partitioned between water and dichloromethane. The layers were separated and the aqueous extracted 2× w/DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated via rotary evaporation to give 116 g amber oil. The crude was purified by automated silica gel chromatography (750 g SiO2, EtOAc/hexanes) to give nearly colorless oil which solidified to white solid upon cooling (99.7 g, 99%).
Reaction SMILES: [ClH:1].Cl.[N:3]1[NH:4][N:5]=[N:6][C:7]=1[C:8]1[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=1.[SH:16][CH2:17][C:18](O)=O>Cl>[ClH:1].[N:6]1[NH:5][N:4]=[N:3][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:18]([CH2:17][SH:16])=[N:15][C:10]=2[CH:9]=1
Reactant: Nc1ccc(-c2nn[nH]n2)cc1N
Reactant: O=C(O)CS
Agent: Cl
Product: SCc1nc2cc(-c3nn[nH]n3)ccc2[nH]1
Temperature: 110 °C
Yield: 56.8 %

Procedure:
To 4-(2H-tetrazol-5-yl)-benzene-1,2-diamine dihydrochloride (9.40 g, 37.7 mmol) in 50% (v/v) hydrochloric acid (105 ml). 2-mercaptoacetic acid (2.4 ml, 3.18 g, 34.5 mmol) was added and the reaction mixture heated under nitrogen at 110° C. for 48 hours. Additional mercaptoacetic acid (0.5 ml, 0.66 g, 7.20 mmol) was added after 24 hours. The reaction mixture was cooled and a sample analysed by hplc. The greenish coloured solid was filtered off and washed with water. The solid was dried at 50° C. under a vacuum (90 mBar) to yield [5-(2H-tetrazol-5-yl)-1H-benzoimidazol-2-yl]-methanethiol hydrochloride (5.27 g, 65% yield), Rt=7.4 mins, purity by HPLC>97%. 1H NMR (d6-DMSO, 400 MHz) 8.49 ppm (1H, m), 8.22 ppm (1H, dd, 8.8 Hz, 1.6 Hz), 7.95 ppm (1H, m, 9.2 Hz), 4.67 ppm (0.3H, s), 4.24 ppm (2H, s). MS: (Electrospray+) 233.0 m/z (M+H), 463.0 m/z (2M−H).