Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:21][C:17]2[N:16]=[CH:15][C:14]([CH:12]([N:9]3[C:10](=[O:11])[C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:30]([O:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:31])[C:7]=4[CH2:8]3)[CH3:13])=[CH:19][C:18]=2[CH3:20])=[CH:24][CH:25]=1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCc1ccc(F)cc1
Reactant: O=COc1ccccc1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCc1ccc(F)cc1
Yield: 86 %

Procedure:
The title compound is prepared in 86% yield (287 mg, brown oil) from 4-chloro-2-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (276 mg, 0.67 mmol, Intermediate-125, single enantiomer) and phenyl formate (164 mg, 1.34 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([CH:7]=1)[O:8][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Oc1cc(Br)cc(F)c1F
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cc(Br)cc(F)c1F
Temperature: 80 °C
Yield: 91 %

Procedure:
To a solution of 5-bromo-2,3-difluorophenol (Avocado, 2.5 g, 12.0 mmol) in DMF (50 mL) was added ethyl 4-bromobutyrate (2.57 g, 13.2 mmol) and K2CO3 (2.5 g, 18 mmol). The reaction mixture was heated at 80° C. for 3 hours. The reaction mixture was diluted with EtOAc and washed with water (3×) and brine, dried (MgSO4) and concentrated under vacuum affording the title compound as a colorless oil (3.53 g, 91%). 1H NMR (DMSO-d6, 300 MHz) δ 7.36 (m, 1H), 7.28 (m, 1H), 4.16-4.03 (m, 4H), 2.45 (t, 2H), 2.03-1.94 (m, 2H), 1.18 (t, 3H). LC/MS (Method B): 323.1, 325.0 (M+H)+. HPLC (Method A) Rt 4.94 min (Purity: 99.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].[I:11]Cl>C(Cl)Cl>[NH2:1][C:2]1[C:9]([I:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10]
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: ClI
Solvent: ClCCl
Product: N#Cc1cc(Cl)c(N)c(I)c1
Reaction time: 12 h
Yield: 35.5 %

Procedure:
4-Amino-3-chloro-benzonitrile (100 mg, 0.66 mmol) and ICl (1.1 eq, 0.72 mmol, 117.05 mg) were added in methylene chloride. The reaction mixture was stirred for 12 hr. The reaction mixture was purified according to similar procedure to step 2 of Example 8 to obtain 4-Amino-3-chloro-5-iodobenzonitrile (65.2 mg, 35.80%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:7][S:8](Cl)(=[O:10])=[O:9]>[OH-].[Na+]>[CH3:7][S:8]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: NCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)NCCC(=O)O
Reaction time: 3 h

Procedure:
22.3 g of β--alanine are dissolved in 125 ml of 2N NaOH. 20 ml of methanesulfonyl chloride and 145 ml of 2N NaOH are simultaneously added dropwise at 0°-5° C., with vibromixing, and the mixture is vibrated at room temperature for 3 hours. The solution is extracted with ether and the extract is diluted to 400 ml and stirred with a strongly acid ion exchanger (Lewatit® S 100) until the pH reaches about 2. The solution is then evaporated to dryness in vacuo. The residue is taken up in ethyl acetate, the mixture is dried over sodium sulfate and DCA is added until an alkaline reaction is obtained. The precipitate which separates out is filtered off, washed with ethyl acetate and ether, dried and recrystallized from tetrahydrofuran.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][C:4]=1[F:32].[C:33]([O:37][C:38]([NH:40][S:41](N1C=CC(=[N+](C)C)C=C1)(=[O:43])=[O:42])=[O:39])([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>ClCCl>[F:32][C:4]1[CH:5]=[C:6]([CH:9]([CH3:31])[C:10](=[O:11])[NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])(=[O:42])=[O:43]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)c(F)c2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)c(F)c2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-(4-(Aminomethyl)-3-fluorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide and intermediate (A) are dissolved in dichloromethane, dropwise triethylamine (0.1 equiv.). The reaction is stirred for 15 h at room temperature and quenched with water. The organic layer is extracted by dichloromethane and concentrated. After purification, tert-butyl N-(2-fluoro-4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzyl)sulfamoylcarbamate is obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[N:13][C:14]([NH2:26])=[C:15]([C:17]2[S:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH:16]=1)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[C:15]([C:17]2[S:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[C:14]([NH2:26])=[N:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-prop-2-ynyl]-carbamic acid tert-butyl ester (0.225 g, 0.6 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (0.5 mL, 6 mmol), the mixture was stirred at RT for 2 h. Aq. satd. NaHCO3 (20 mL) was added, and the mixture was extracted with CH2Cl2/MeOH (10%, 4×30 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated at reduced pressure to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=3.78 (s, 2H), 7.42-7.58 (m, 2H), 7.88 (d, J=6.8 Hz, 1H), 8.05-8.07 (m, 2H), 8.32 (d, J=1.8 Hz, 1H). MS (ES+): m/z=281.14 (100) [MH+]. HPLC: tR=2.01 min (ZQ2, polar—5 min).
Reaction SMILES: N.C([N:9]1[C@H:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][C@H:11]([CH2:21][CH2:22][C:23]2([CH3:28])[O:27][CH2:26][CH2:25][O:24]2)[C:10]1=[O:29])C1C=CC=CC=1.[Li]>C1COCC1.CO>[CH2:14]([C@H:13]1[NH:9][C:10](=[O:29])[C@@H:11]([CH2:21][CH2:22][C:23]2([CH3:28])[O:27][CH2:26][CH2:25][O:24]2)[CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(CC[C@H]2C[C@@H](Cc3ccccc3)N(Cc3ccccc3)C2=O)OCCO1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(CC[C@H]2C[C@@H](Cc3ccccc3)NC2=O)OCCO1
Reaction time: 0.33 h

Procedure:
Into a 3-necked 500 mL flask at -78° C. was condensed 100 mL of ammonia. Next, 12-2 (470 mg, 1.24 mmol), dissolved in 20 mL of THF, was added. Lithium (19 mg, 2.48 mmol) was washed with MeOH, then THF and then added to the ammonia. After 20 minutes, the reaction was quenched with NH4Cl; 200 mL of THF was added, the cooling bath was removed and the solution purged with argon for 30 minutes to remove the ammonia. The solution was dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc) gave 12-3 as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(#N)C>[N+:8]([C:7]1[C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C1CNCCN1
Solvent: CC#N
Product: O=[N+]([O-])c1cccnc1N1CCNCC1

Procedure:
A solution of 2-chloro-3-nitropyridine (4.76 g, 30 mmol) and piperazine (5.9, 69 mmol) in acetonitrile, (75 mL), was stirred at reflux for 5 h. After concentrating under reduced pressure, the residue was partitioned between ethyl acetate and 10% NaOH. The ethyl acetate extract was washed with water, dried (Na2SO4), filtered and concentrated. Flash chromatography over Al2O3 and elution with 2% MeOH-98% CHCl3 afforded the title compound, m.p. 82°-87° C. An analytical sample, m.p. 83.5°-86.5° C., was obtained upon recrystallization from CHCl3 -hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH2:14])=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[N:15]1([C:20](N2C=CN=C2)=[S:21])[CH:19]=[CH:18][N:17]=[CH:16]1>C(#N)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([NH:14][C:20]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[S:21])=[N:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cnc(N)s2)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(-c2cnc(NC(=S)n3ccnc3)s2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
To 5-(4-methoxyphenyl)thiazol-2-amine (1.07 g, 5.19 mmol) in acetonitrile (30 mL) and tetrahydrofuran (5 mL) was added di(1H-imidazol-1-yl)methanethione (1.20 g, 6.74 mmol). The reaction was stirred at 60° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered. The powder was washed with cold acetonitrile (2×15 mL) and dried to yield N-(5-(4-methoxyphenyl)thiazol-2-yl)-1H-imidazole-1-carbothioamide (0.59 g, 1.86 mmol, 35.9% yield) as a orange-brown powder. The product was taken directly to the next step without any further characterization.
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](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]2Cl.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]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](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]2[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH2:21]1
Reactant: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)-3-methylbutan-1-one (309 mg, 0.950 mmol) was reacted with tert-butyl trans-4-aminocyclohexylcarbamate (407 mg, 1.90 mmol) to afford the desired product (267 mg, 56%) as a yellow solid: ESI MS m/z 504 [C20H26BrN3O+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][CH2:11][OH:12].[H][H]>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: [H][H]
Reactant: OCCCC#Cc1ccccn1
Agent: [Pd]
Solvent: CCO
Product: OCCCCCc1ccccn1
Yield: 93.1 %

Procedure:
5-(2-Pyridinyl)-4-pentyn-1-ol (8.8 g) was hydrogenated over 1.0 g of 10% Pd/C in 125 mL of ethanol at room temperature and atmospheric pressure. After the uptake of hydrogen had stopped, the catalyst was removed by filtration and the solvent was removed under reduced pressure. The residual oil was distilled on a Kugelrohr apparatus (115°-120° C./0.1 mm) to yield 8.4 g of 2-pyridinepentanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:17]=[C:16]([NH2:26])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2].[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH:42]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[CH2:1]([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:21][CH2:22][N:23]([CH2:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)[CH2:24][CH2:25]3)[N:17]=[C:16]([NH2:26])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(Oc2cc(N3CCNCC3)nc(N)n2)cc1)Oc1ccccc1
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)(Cc1ccc(Oc2cc(N3CCN(Cc4ccccn4)CC3)nc(N)n2)cc1)Oc1ccccc1
Temperature: 25 °C

Procedure:
To a stirring solution of 3-[4-(2-Amino-6-piperazin-1-yl-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionic acid ethyl ester (1 mmol) in dry dichloromethane (20 ml) under N2 was added pyridine-2-carbaldehyde (1.1 mmol). The reaction was stirred at room temperature for half an hour, then Sodium triacetoxyborohydride (1.3 mmol) was then added and stirred over night. Water (10 mL), the biphasic mixture was diluted with dichloromethane and partitioned, and the organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified in silica to provide yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][C:14](O)=[O:15])[N:10]([CH2:17][CH3:18])[N:9]=2)=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][C:14]([Cl:27])=[O:15])[N:10]([CH2:17][CH3:18])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCn1nc(-c2ccc(Cl)cc2)nc1CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1nc(-c2ccc(Cl)cc2)nc1CC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.2 mmol (318 mg) of [3-(4-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-5-yl]acetic acid and 0.1 mmol (7 mg) of DMF are dissolved in 5 ml of anhydrous dichloromethane 1.3 mmol of oxalyl chloride (163 mg) in 3 ml of anhydrous dichloromethane are added dropwise. The solution is stirred at room temperature for 8 h and then concentrated under reduced pressure. The [3-(4-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-5-yl]acetyl chloride obtained in this manner is processed further in crude form.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.C(O)=O>CO.[Pd]>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Oc1cccnc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: Cc1ccc(N)cc1Oc1cccnc1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A solution of 3-(2-methyl-5-nitrophenoxy)pyridine (80 mg, 0.35 mmol) and 10% Pd/C (50% wet, 165 mg, 0.08 mmol) in methanol (4 mL) was treated with formic acid (89%, 1 mL, 35 mmol) and the resultant solution was stirred at RT. After 1 h, the reaction mixture was filtered through Celite®, and the filter cake was washed with methanol. The filtrates were concentrated in vacuo, diluted with 40 mL of a pH 12 aqueous solution and extracted with ethyl acetate (3×25 mL). The extracts were dried (Na2SO4) and concentrated in vacuo to provide 4-methyl-3-(pyridin-3-yloxy)benzenamine (58 mg, 83% yield). 1H NMR (400 MHz, CDCl3) δ 8.36 (m, 2H), 8.32 (dd, J=4.6, 1.4 Hz, 1H), 7.26-7.18 (m, 3H), 7.05 (d, J=8.0 Hz, 1H), 6.49 (dd, J=8.8, 2.4 Hz, 1H), 6.29 (d, J=2.4 Hz, 1H), 2.11 (s, 3H); MS (ESI) m/z: 201.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1I)[CH:7]=[O:8])[CH3:2].C(O[C:16](=O)[C:17]1[CH:22]=CC(I)=C(OCC)C=1)C.CC(C[AlH]CC(C)C)C>O=[Mn]=O>[CH:22]1([C:11]2[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=2[O:3][CH2:1][CH3:2])[CH2:17][CH2:16]1
Reactant: CCOc1cc(C=O)ccc1I
Reactant: CCOC(=O)c1ccc(I)c(OCC)c1
Agent: O=[Mn]=O
Agent: CC(C)C[AlH]CC(C)C
Product: CCOc1cc(C=O)ccc1C1CC1

Procedure:
The necessary intermediate 4-Cyclopropyl-3-ethoxy-benzaldehyde was prepared as described in example 158, but using 3-ethoxy-4-iodo-benzaldehyde (synthesized from 3-ethoxy-4-iodo-benzoic acid ethyl ester (CAS NO. 741699-04-7) by DIBAL-H reduction followed by MnO2 oxidation) as starting material, as light brown oil.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][SH:5].[CH2:7]([CH:9]1[O:11][CH2:10]1)[Cl:8]>>[Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][S:5][CH2:10][CH:9]([OH:11])[CH2:7][Cl:8]
Reactant: ClCC1CO1
Reactant: OC(CS)CCl
Product: OC(CCl)CSCC(O)CCl

Procedure:
Epichlorohydrin (5563 g, 60.12 mol) and methanol (2500 g) were put into a 10-liter reactor. The reaction temperature was adjusted to 6° C. When the reaction temperature reached 6° C., sodium hydroxide (50% aq., 5 g) was added to the mixture. NaSH.xH2O (70% NaSH, 3660 g, 45.75 mol), methanol (1000 g) and water (500 g) were completely dissolved with stirring in another 10-liter reactor, and hydrochloric acid was slowly added dropwise thereto to generate hydrogen sulfide gas. The hydrogen sulfide gas was added to the epichlorohydrin solution to obtain bis(3-chloro-2-hydroxypropyl)sulfide. The completion of the reaction was defined as the time when epichlorohydrin and 3-chloro-2-hydroxy-propane-1-thiol disappeared completely and bis(3-chloro-2-hydroxypropyl)sulfide was formed, which was confirmed by GC. When 3-chloro-2-hydroxy-propane-1-thiol was present, the content of the thiol compound was calculated from the relative integral ratio by GC and epichlorohydrin was further added in an amount corresponding to the calculated content. The reaction of epichlorohydrin and the thiol compound afforded bis(3-chloro-2-hydroxypropyl)sulfide (BCPS).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:30][C:31]1[CH:32]=[CH:33][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[N:35][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:40][S:37]([C:34]2[CH:33]=[CH:32][C:31]([CH3:30])=[CH:36][N:35]=2)(=[O:39])=[O:38])=[O:27])=[CH:28][CH:29]=1)[CH3:20])=[O:17]
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Reactant: Cc1ccc(S(N)(=O)=O)nc1
Product: Cc1ccc(S(=O)(=O)NC(=O)c2ccc([C@H](C)NC(=O)c3cc(Cl)cnc3Oc3ccc(F)cc3)cc2)nc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 103 from 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44) and 5-methylpyridine-2-sulfonamide: 1H-NMR (DMSO-d6) δ 8.95 (1H, d, J=8.6 Hz), 8.38 (1H, br.s), 8.26 (1H, d, J=2.6 Hz), 8.10 (1H, d, J=2.6 Hz), 7.92–7.70 (4H, m), 7.40 (2H, d, J=7.9 Hz), 7.30–7.23 (4H, m), 5.22–5.08 (1H, m), 2.34 (3H, s), 1.44 (3H, d, J=6.8 Hz); MS (ESI) m/z 569 (M+H)+, 567 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH2:45]([NH2:49])[CH:46]([CH3:48])[CH3:47]>CN(C=O)C>[CH2:45]([NH:49][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:22])[CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)CN
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCC(C)C)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 Mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and isobutylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(isobutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:11])([CH3:10])[CH3:9])(=O)=O.[CH3:14][C:15]1([CH3:42])[NH:27][CH:26]([C:28]2[C:33]([F:34])=[CH:32][C:31](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])=[CH:30][C:29]=2[F:41])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:34][C:33]1[CH:32]=[C:31](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])[CH:30]=[C:29]([F:41])[C:28]=1[CH:26]1[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][C:15]([CH3:14])([CH3:42])[N:27]1[CH2:7][C:8]([F:11])([CH3:9])[CH3:10])=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: COC(=O)/C=C/c1cc(F)c(C2NC(C)(C)Cc3c2[nH]c2ccccc32)c(F)c1
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1cc(F)c(C2c3[nH]c4ccccc4c3CC(C)(C)N2CC(C)(C)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
2-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 1, preparation of starting materials) (679 mg, 3.03 mmol) was added to a solution of (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate (obtained as described in Example 5, preparation of starting materials) (600 mg, 1.51 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.915 ml, 5.30 mmol) in 1,4-dioxane (2.5 ml). The reaction was stirred at room temperature for 1 h. The reaction was then heated to 105° C. for 88 hours. The volatiles were removed under vacuum and the crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(3,5-difluoro-4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (430 mg, 60.4%) as a white solid. The racemic product was purified by preparative HPLC (Chiralpak AD column, 20 μm silica, 50 mm diameter, 250 mm length), Heptane:Ethanol 90:10 90 ml/min. Fractions containing the desired compounds were evaporated to dryness to afford (E)-methyl 3-(3,5-difluoro-4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1, first eluted, 149 mg, 34.6%) and (E)-methyl 3-(3,5-difluoro-4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 2, second eluted, 143 mg, 33.3%) as cream coloured solids. 1H NMR (400 MHz, CDCl3, 30° C.) δ 1.01 (3H, d), 1.08 (3H, s), 1.15 (3H, d), 1.34 (3H, s), 2.55 (1H, dd), 2.66 (1H, d), 2.98-3.06 (1H, m), 3.17 (1H, dd), 3.80 (3H, s), 5.23 (1H, s), 6.38 (1H, d), 6.97 (2H, d), 7.07-7.12 (2H, m), 7.17-7.22 (1H, m), 7.32 (1H, s), 7.46-7.5 (1H, m), 7.52 (1H, d). m/z ES− [M−H]− 469.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=CCc1ccc(Br)cc1
Temperature: -78 °C

Procedure:
To a cold solution (-78° C.) of 15 g (62 mmol) of ethyl (4-bromophenyl)acetate (Compound A) in 150 ml of CH2Cl2 was added dropwise (over a span of 1 hour) 65 ml (65 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition was complete, the reaction was stirred at -78° C. for an additional hour. The reaction was quenched by the dropwise addition of methanol (10 ml), followed by water (10 ml) and 10% HCl (40 ml). The mixture was then warmed to 0° C., stirred for 10 minutes and then washed with water (15 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml). The organic phase was dried over MgSO4 and the solvent distilled off at ambient temperature to give crude (4-bromophenyl)acetaldehyde. To a cold solution (0° C.) of this crude aldehyde in 150 ml of CH2Cl2 was added a solution of 26 g (74.6 mmol) of (carbethoxymethylene)triphenylphosphorane in 50 ml of CH2Cl2. The mixture was stirred for 16 hours, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to give ethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. This isomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over 1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a white solid.