Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.FC(F)(F)C(O)=O.[CH2:20]([C:22]1[S:23][CH:24]=[C:25]([C:27]([N:29]2[CH2:34][C:33]3([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[O:32][CH2:31][CH2:30]2)=[O:28])[N:26]=1)[CH3:21].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:37]1[CH2:38][CH2:39][C:33]2([O:32][CH2:31][CH2:30][N:29]([C:27]([C:25]3[N:26]=[C:22]([CH2:20][CH3:21])[S:23][CH:24]=3)=[O:28])[CH2:34]2)[CH2:35][CH2:36]1
Reactant: O=Cc1cccc(CCO)c1Cl
Reactant: CCc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4Cl)CC3)C2)cs1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-chloro-3-(2-hydroxyethyl)benzaldehyde [Aromatic Intermediate 11] (1.5 g) and (2-ethylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Example 26, step b] (4.25 g) in tetrahydrofuran (50 mL) was added triethylamine (2.5 mL) in one portion. The mixture was stirred for 0.5 h, sodium triacetoxyborohydride (2.58 g) was then added in one portion and the resultant solution was stirred for 2 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate solution (50 mL). The mixture was shaken vigorously for 10 min and the layers were separated. The aqueous phase was extracted with ethyl acetate (100 mL). The combined organic solutions were washed with brine, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash silica chromatography using 95:5 ethyl acetate:triethylamine as solvent. The fractions containing the product were combined and evaporated to give the subtitled compound as a clear oil. Yield 3.40 g.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].CCO>O>[CH3:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:25]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
The mixture of 2-(2,3-dimethyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (235) (290 mg, 0.86 mmol), KOH (50% aqueous solution, 1.92 g, 17.2 mmol), EtOH (10 mL) and water (1 mL) are stirred in a 20 mL vial at 50° C. for 30 min. After concentration in vacuo, the residue is dissolved in water (5 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The filtration gives 2-(2,3-dimethyl-benzoylamino)-indan-2-carboxylic acid (236) as white solid (240 mg, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]=[N+:13]=[N-:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(F)cc1

Procedure:
Suspend 4-fluorobenzenesulfonyl chloride (0.500 g, 2.57 mmol) and sodium azide (0.200 g, 3.08 mmol) in acetone. Heat at reflux overnight before concentrating the reaction mixture. Purify by flash 40 chromatography, eluting with 10% ethyl acetate in hexanes to give the title compound: 1H NMR (DMSO-d6) δ 7.58 (tt, J=8.04, 2.02 Hz, 2H), 8.12 (td, 4.89, 1.96 Hz, 2H); HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 50-99% over 19 min], tR=16.5 min, 92.4% purity.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:16])([CH2:14][NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[O:25].C1(C)C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([O:16][C:24](=[O:25])[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1(O)CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1NCC2(CCN(Cc3ccccc3)CC2)O1
Reaction time: 15 h

Procedure:
To a solution of crude 1-benzyl-4-hydroxy-4-aminomethyl piperidine, as described above in Step A, (˜3.1 gm, 12 mmol) in acetonitrile (50 mL) containing triethyl amine (5.7 mL, 42 mmol) cooled in an ice bath was added in 1 mL portions 20% phosgene/toluene (9 mL) over a three hour period. The reaction mixture was stirred at ambient temp. for 15 hours and diluted with ethyl acetate. This solution was washed with water (2×) and the organic layer dried (anhyd. sodium sulfate), filtered, and the solvent removed under vacuum. The residue was triturated with diethyl ether and the title compound collected by filtration as a white solid, mp: 159-161° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:9]([OH:11])=O)[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22].[C:27]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH-:34])=[CH:31][CH:30]=1)#[N:28].[ClH:37]>>[NH2:1][C@@H:2]([C:9]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:11])[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1.[C:27]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH-:34])=[CH:31][CH:30]=1)#[N:28].[ClH:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CCCCC1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: N#Cc1ccc(C[NH-])cc1
Product: N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1

Procedure:
Firstly H-(D)-Chg-Pro-p-cyanobenzylamide×HCl was prepared from Boc-(D)-Chg-OH and H-Pro-p-cyanobenzylamide×HCl as in Example 3.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[CH3:12][N:13]([CH3:19])[C@@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1>>[CH3:12][N:13]([CH3:19])[C@@H:14]1[CH2:18][CH2:17][N:16]([C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH2:15]1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Reactant: CN(C)[C@@H]1CCNC1
Product: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Yield: 68.8 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (536 mg, 3.50 mmol) reacted with (3R)-(+)-3-dimethylamino-pyrrolidine (480 mg, 4.20 mmol) to give 3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (600 mg, 69%).
Reaction SMILES: CN(/[CH:4]=[C:5]1\[CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH2:9][C:10]\1=O)C.[CH3:19][CH:20]([NH:22][NH2:23])[CH3:21]>>[CH3:19][CH:20]([N:22]1[CH:4]=[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:10]2=[N:23]1)[CH3:21]
Reactant: CC(C)NN
Reactant: CN(C)/C=C1\CN(C(=O)OC(C)(C)C)CCC1=O
Product: CC(C)n1cc2c(n1)CCNC2

Procedure:
tert-Butyl (3E)-3-[(dimethylamino)methylidene]-4-oxopiperidine-1-carboxylate was condensed with propan-2-ylhydrazine; removal of the protecting group provided 2-(propan-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.
Reaction SMILES: [Br:1][C:2]1(Br)[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:9].C([O-])(=O)C.[Na+]>[Pd].C(O)(=O)C>[Br:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:9]
Reactant: O=C1NCCCCC1(Br)Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NCCCCC1Br
Yield: 95.3 %

Procedure:
A solution of 16 g (59 mmol) of 3,3-dibromoazacycloheptan-2-one, 150 ml of glacial acetic acid, 5.5 g (65 mmol) of sodium acetate, and 0.5 g of palladium on carbon (10%) was placed in a hydrogenator bottle and reduced under hydrogen at 30 psi. The mixture was filtered, and the filtrate distilled under vacuum to remove the acetic acid. The residue was neutralized with sat. Na2CO3, extracted into CH2Cl2, dried over MgSO4, and concentrated to yield 10.8 g (95%) of the product as an off-white solid; mp 109°-111° C.; NMR (CDCl3) 7.2 (1 H,m), 4.6 (1 H,m), 3.4 (2 H,m), 2.1 (4 H,m), 1.7 (2 H,m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]2[O:9][C:8]([CH2:10][CH2:11][OH:12])=[CH:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:12][CH2:11][CH2:10][C:8]2[O:9][C:5]3[C:4]([Cl:14])=[CH:3][C:2]([Br:1])=[CH:13][C:6]=3[CH:7]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1cc2cc(Br)cc(Cl)c2o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)cc(Cl)c3o2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.5 %

Procedure:
To a solution of the product of step B (3.5 g, 12.7 mmol) in dichloromethane (30 mL) was added triethylamine (3.7 mL, 25.4 mmol) followed by p-toluenesulfonyl chloride (3.6 mL, 19.05 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 12 h and concentrated in vacuo. The reaction mixture was quenched with saturated sodium bicarbonate solution, washed with 0.5 N HCl and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 4:1 hexanes/ethyl acetate) providing 2-(5-bromo-7-chlorobenzofuran-2-yl)ethyl 4-methylbenzenesulfonate (5.1 g, 95%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.66-7.62 (m, 2H), 7.49 (d, J=2.0 Hz, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.18-7.14 (m, 2H), 6.43 (s, 1H), 4.39 (t, J=6.4 Hz, 2H), 3.14 (t, J=6.0 Hz, 2H), 2.37 (s, 3H).
Reaction SMILES: [N:1]1([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:17])(=[O:16])=[O:15])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.ClCCl.C[Al](C)C.C[O:26][C:27](=O)[NH:28][C:29]1[N:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([O:37][CH3:38])[N:30]=1>C1(C)C=CC=CC=1>[N:1]1([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH:17][C:27]([NH:28][C:29]2[N:30]=[C:31]([O:37][CH3:38])[N:32]=[C:33]([O:35][CH3:36])[N:34]=2)=[O:26])(=[O:16])=[O:15])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccccc1S(=O)(=O)N1CCC1
Reactant: COC(=O)Nc1nc(OC)nc(OC)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)N2CCC2)nc(OC)n1
Yield: 23.8 %

Procedure:
In a dry flask under nitrogen was placed 1.20 gram of 2-(azetidin-1-ylsulfonyl)benzenesulfonamide, 50 ml of dry dichloromethane and 2.48 ml of 2M trimethylaluminum in toluene. To this was added 0.885 g of 4,6-dimethoxy-1,3,5-triazin-2-ylcarbamic acid methyl ester and the resultant solution was heated to reflux for 12 hours. The solution was washed with 50 ml of a water/acetic acid/1N HCl solution (40:10:0.4). The organic fraction was concentrated and chromatographed on silica gel (ethyl acetate/methylene chloride (15:85)). The slower moving portions were collected, treated with ethyl acetate and dried to give 0.45 g of a solid, m.p. 175°-177° C.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]=2)[CH2:6]1)=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][NH:5][CH2:14][CH2:13]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCCCc1ccc2c(c1)CCNC2
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A mixture of the product of Step D (0.1 g; 0.29 mmol) and K2CO3 (0.04 g; 0.29 mmol) in 50% aqueous MeOH (5 ml) was refluxed for 3 h, under N2, then cooled to room temperature. The organic solvent was removed under reduced pressure and the residue was diluted to 15 ml with Et2O, washed with, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give a title compound (0.07 g; 98%), as a colourless syrup. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=6.9 Hz); 1.26 (m, 10H); 1.56 (m, 2H); 2.52 (tr, 3H, J=6.9 Hz); 2.71-2.8 (m, 2H); 3.08-3.16 (m, 2H); 3.96-4.01 (m, 2H); 6.8-7.07 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][NH:12][C:11](=[O:17])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH:18]1([C:21]2[N:22]=[C:23]3[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]3[C:32]=2[CH3:33])[CH2:20][CH2:19]1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][N:12]([C:26]4[CH:27]=[CH:28][C:23]5[N:24]([C:32]([CH3:33])=[C:21]([CH:18]6[CH2:20][CH2:19]6)[N:22]=5)[CH:25]=4)[C:11](=[O:17])[C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1c(C2CC2)nc2ccc(B(O)O)cn12
Reactant: O=c1[nH]ccc2oc(-c3ccc(Cl)cc3)cc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc4oc(-c5ccc(Cl)cc5)cc4c3=O)cn12
Temperature: 50 °C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
A mixture of 2-(4-chlorophenyl)furo[3,2-c]pyridin-4(5H)-one (100 mg), (2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)boronic acid (106 mg), copper(II) acetate (4.99 mg), pyridine (0.066 mL), MS-4A (48.9 mg) and DMF (5.0 mL) was stirred at room temperature for 4 hr and at 50° C. overnight. After filtration of the obtained mixture through Celite, the filtrate was poured into 1 N hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained solid was washed with ethanol to give the title compound (10.0 mg) as a pale brown solid.
Reaction SMILES: [CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[O:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:30][N:31](C)[CH:32]=O>>[CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([N:31]([CH3:32])[CH3:30])=[O:13])=[CH:10][C:9]=1[O:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCCCOc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCOc1cc(C(=O)N(C)C)cc(S(N)(=O)=O)c1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A mixture of 4-benzyl-3-n-butoxy-5-sulfamylbenzoic acid (3.6 g), thionyl chloride (20 ml) and N,N-dimethylformamide (0.1 ml) is refluxed for 1 hour and is then evaporated in vacuo. The resulting crude 4-benzyl-3-n-butoxy-5-sulfamylbenzoyl chloride is dissolved in methylene chloride (30 ml), and the resulting solution is during about 15 minutes added dropwise to a stirred mixture of dimethylamine (10 ml; 40% in water) and methylene chloride (20 ml), keeping the temperature at 0°-5° C. by external cooling. After stirring for an additional 2 hours at 22°-25° C., the mixture is washed with water and the organic layer is separated and dried in the presence of magnesium sulphate. Filtration followed by evaporation in vacuo yields crude 4-benzyl-3-n-butoxy-5-sulfamyl-N,N-dimethylbenzamide. After recrystallization from benzene it is obtained with a melting point of 199°-201° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14]>CN(C)C(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: CCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1cn2nc(I)ccc2n1
Yield: 72.3 %

Procedure:
Using 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.0 g, 3.85 mmol), N,N-dimethylacetamide (10 mL) and propionyl chloride (0.37 mL, 4.23 mmol) as starting materials and in the same manner as in Reference Example 5, the title compound (0.88 g, 72%) was obtained as a dark brown powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC[C@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1C[C@@H](O)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 83.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (66.5 mg, 0.0975 mmol) prepared in Example 162h, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (39.2 mg, 83%) as a colorless solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1.C(N(CC)CC)C>C(#N)C.C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=3)=[O:25])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: NCc1ccccn1
Reactant: CCCc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)NCc2ccccn2)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 200 mg (0.371 mmol) of N-(4-isopropylbenzenesulfonyl)-α-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetamide (from Step D) in 2 mL of acetonitrile and 1 mL of dry THF was added 72.2 mg (0.445 mmol) of 1,1'-carbonyldiimidazole. The solution was stirred under N2 at 60° C. for 2 hours. Then 45.9 μL (48.1 mg; 0.445 mmol) of 2-(aminomethyl)pyridine was added, followed by 129 μL (93.7 mg; 0.928 mmol) of triethylamine. The solution was stirred overnight at 60° C. The cooled reaction mixture was quenched by addition of 5% citric acid solution (aqueous) and extracted twice with EtOAc. The combined organic extracts were washed twice with H2O, then with brine, dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was flash chromatographed (gradient elution with 1-6% MeOH in CH2Cl2) to give 191 mg (82%) of the title compound as a cream-colored solid, mp 168°-170° C.; homogeneous by TLC in 95:5 CH2Cl2 -MeOH. ESI mass spectrum m/e 630 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[O:27][CH2:28][CH2:29][O:30][CH3:31]>CN(C=O)C.CCOC(C)=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[C:21]([O:27][CH2:28][CH2:29][O:30][CH3:31])[CH:22]=2)[N:7]=1
Reactant: COCCOc1cc(N)ccc1OC
Reactant: Clc1ncnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc(Nc2ncnc(Cl)n2)ccc1OC
Temperature: 0 °C
Reaction time: 0.38 h

Procedure:
2,4-Dichloro-1,3,5-triazine (89.1 mg, 0.5944 mmol) was dissolved in DMF (0.5 ml) and cooled to 0° C. To this solution were added DIEA (104 μl), 4-methoxy-3-(2-methoxy-ethoxy)phenylamine (TFA salt)(264 mg, ˜0.59 mmol) and DIEA (208 μl) in DMF (1 ml). The reaction mixture was kept at 0° C. for 15 to 30 min and then at RT for 15 min to 2 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered, and evaporated in vacuo, to give (4-chloro-[1,3,5]triazin-2-yl)-[4-methoxy-3-(2-methoxy-ethoxy)-phenyl]amine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].Br.Br[CH2:14][C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:16].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[O:16]=[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:14][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc[nH]1
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1CC(=O)c1cccnc1
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
To a chilled solution of methyl 2-pyrrole carboxylate (200 mg, 1.6 mmol) in dry DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 160 mg, 4.0 mmol) portionwise under nitrogen. Extra DMF (2 mL) was added and the suspension was stirred for 30 minutes. 3-(Bromoacetyl)pyridine hydrobromide (600 mg, 2.1 mmol) was added portionwise and the mixture was allowed at room temperature and stirred overnight. Saturated aqueous solution of aqueous NH4Cl (10 mL) followed by EtOAc (30 mL) were added. The organic layer was washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give an orange liquid that was purified by flash chromatography (Biotage SP4, 40 g cartridge, gradient 0-80% EtOAc in hexanes) to yield methyl 1-[2-oxo-2-(pyridin-3-yl)ethyl]-1H-pyrrole-2-carboxylate as a colourless oil (75 mg, yield 19%). 1H-NMR (400 MHz, CDCl3): δ 3.72 (s, 3H), 5.72 (s, 2H), 6.26 (dd, 1H, J 4.0, 2.6 Hz), 6.85 (dd, 1H, J 2.6, 1.8 Hz), 7.04 (dd, 1H, J 4.0, 1.8 Hz), 7.46 (ddd, 1H, J 7.9, 4.8, 0.8 Hz), 8.25-8.28 (m, 1H), 8.83 (dd, 1H, J 4.8, 1.7 Hz), 9.21 (dd, 1H, J 0.8, 2.2 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.Br[CH:21](C1C=CC=CC=1)C>>[CH3:14][O:13][C:10]1[C:9]([O:15][CH3:16])=[CH:8][C:7]([S:6][CH:5]([C:4]2[CH:17]=[CH:18][CH:19]=[CH:2][CH:3]=2)[CH3:21])=[CH:12][N:11]=1
Reactant: CC(Br)c1ccccc1
Reactant: COc1cc(SCc2cccc(Cl)c2)cnc1OC
Product: COc1cc(SC(C)c2ccccc2)cnc1OC

Procedure:
Prepared as described for 5-(3-chlorobenzylthio)-2,3-dimethoxypyridine (Intermediate 8) but using (1-bromoethyl)benzene instead of 1-(bromomethyl)-3-chlorobenzene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:28][C:29]1[C:30](Cl)=[N:31][CH:32]=[CH:33][CH:34]=1>CO>[Br:28][C:29]1[C:30]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=4)=[O:16])[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1cccc(N)c1
Reactant: Clc1ncccc1Br
Solvent: CO
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1cccc(Nc2ncccc2Br)c1
Temperature: 180 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
A mixture of 3′-amino-6-methyl-N-[3-(trifluoromethyl)phenyl]biphenyl-3-carboxamide (150 mg, 0.41 mmol) and 3-bromo-2-chloropyridine (90 mg, 0.47 mmol) was heated neat to 180° C. in an oil bath. The temperature was increased to 200° C., and then heating was discontinued and the reaction mixture was allowed to stir for 72 h. The resulting solid was dissolved in methanol and purified by flash column chromatography (eluting with a gradient of 0-40% ethyl acetate in hexanes) to afford product (87 mg, 39%).