Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C@@:6]1([CH3:44])[CH2:10][C@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])(=O)=O.[C:45]([C@@H:48]1[CH2:52][CH2:51][CH2:50][NH:49]1)(=[O:47])[NH2:46]>CN(C)C=O>[C:45]([C@@H:48]1[CH2:52][CH2:51][CH2:50][N:49]1[CH2:44][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])(=[O:47])[NH2:46]
Reactant: C[C@]1(OS(C)(=O)=O)C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CCCN1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 25.3 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)-methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (3.0 g) in dimethylformamide (30 ml) was added (2S)-2-carbamoylpyrrolidine (10.76 g) and the mixture was stirred at 100°-110° C. for 5 hours. The reaction mixture was poured into ice-water (100 ml). The resulting precipitates were collected by filtration and washed with water (100 ml). The precipitates were dissolved in ethyl acetate (80 ml) and the solution was washed with aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloro-methane and acetone (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S ,4S )-2-[(2S)-2-carbamoylpyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (0.78 g).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([O:16][CH3:17])=[C:8]2[C:18](Cl)=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][CH2:22][CH:23]([OH:30])[CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27].C(N(CC)CC)C>C(Cl)Cl>[CH2:26]([N:25]([CH2:24][CH:23]([OH:30])[CH2:22][NH:21][C:18]([C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:15]2[C:10]([C:9]=1[O:16][CH3:17])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:19])[CH2:28][CH3:29])[CH3:27]
Reactant: CCN(CC)CC(O)CN
Reactant: COc1c(C(=O)Cl)n(-c2ccccc2)c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CC(O)CNC(=O)c1c(OC)c2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The resulting ethereal solution of N-phenyl-3-methoxyindole-2-carboxylic acid chloride is added dropwise to a solution of 579 g of 1-amino-2-hydroxy-3-diethylaminopropane and 40 g of triethylamine in 70 ml of methylene chloride, whilst cooling with ice. The reaction mixture is stirred at room temperature for 1 hour and then extracted with dilute hydrochloric acid. The hydrochloric acid extract is rendered alkaline by addition of sodium hydroxide solution and is extracted with ether. The ether solution is washed with water, dried over sodium sulphate and evaporated. 110 g of 2-[3-(N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-methoxy-1-phenylindole remain as an oily base. This base is dissolved in isopropanol and converted into its hydrochloride. Yield: 110 g of the hydrochloride=60.6%, melting point: 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH:22]=[CH:23][C:24]#[N:25])[C:11](=[O:28])[C@@H:10]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H][H]>CCO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH2:22][CH2:23][C:24]#[N:25])[C:11](=[O:28])[C@@H:10]([CH2:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC[C@@H](C=CC#N)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCO
Product: CC[C@@H](CCC#N)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 56 mg (0.106 mmol) of tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopent-1-en-3-yl)-2-oxopiperidin-3-yl)acetate (Example 30, Step A) in 3.5 mL of EtOH) was added 10% palladium on activated carbon (11.30 mg, 10.62 μmol). Then the reaction mixture was subjected to regular hydrogenation with hydrogen. After being stirred under a hydrogen atmosphere at rt for 2 h, the catalyst was filtered using a short plug of silica gel. The plug was washed several times with EtOAc. The combined filtrates were concentrated under reduced pressure to provide the crude title compound as a colorless film which was used in the subsequent reaction without further purification. MS (ESI) 529.2 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=[O:36])[NH:15][C:16]1[CH:17]=[C:18]2[C:34](=[O:35])[NH:33][N:32]=[CH:31][C:20]3=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:22][C:23]([CH:24]=1)=[C:19]23)=O)(C)(C)C.Cl.O1CCOCC1>>[O:35]=[C:34]1[C:18]2[C:19]3[C:20](=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:22][C:23]=3[CH:24]=[C:16]([NH:15][C:14]([C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[O:36])[CH:17]=2)[CH:31]=[N:32][NH:33]1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(NC(=O)[C@H]4CCCCN4)cc1c23

Procedure:
Preparation of the title compound from Intermediate 136(a) (0.16 g, 0.33 mmol) and 4M HCl in dioxane (1.6 mL, 6.6 mmol) was carried out analogously to Example 91. Isolation, also in an analogous manner, included a further trituration with CH2Cl2/diethyl ether and afforded the title compound (0.137 g) as an orange/yellow powder in 96% yield.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH:15]=[CH2:16])[CH:5]=1)[CH3:3].C(N(CC)CC)C.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:36])[NH:1][C@@H:2]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH:15]=[CH2:16])[CH:5]=2)[CH3:3])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: C=Cc1cc(C(C)N)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc([C@@H](C)NC(=O)Nc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 38 %

Procedure:
N-[4-(1-Aminoethyl)-2-vinylphenyl]methanesulfonamide (236.7 mg, 0.985 mmol, 1 eq.) and Triethylamine (274.6 μl, 1.970 mmol, 2 eq.) were added in methylene chloride. The reaction mixture was cooled down to 0° C. 4-tert-Butylphenyl isocyanate (192.5 μl, 1.083 mmol, 1.3 eq.) was added. The reaction mixture was stirred for 40 min. Methylene chloride was removed in vacuo. The residue was purified with column chromatography (n-Hx:EA=2:1) to yield title compound (155.4 mg, 38%) as white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:18])[CH:3]=1.[OH:19][C:20]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:30][CH2:29]1)([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[CH2:21][CH3:22].C(O)(=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+].C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC>C(OCC)C.CC(N(C)C)=O>[CH:15]1([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]3[N:7]=[C:2]([C:25]4[S:24][C:23]([C:20]([C@H:28]5[CH2:33][CH2:32][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:30][CH2:29]5)([OH:19])[CH2:21][CH3:22])=[N:27][CH:26]=4)[CH:3]=[C:4]([CH3:18])[CH:5]=3)[CH:14]=2)[CH2:17][CH2:16]1
Reactant: CCC(O)(c1nccs1)[C@H]1CC[C@H](C(=O)OC)CC1
Reactant: Cc1cc(Br)nc(Nc2cc(C3CC3)ccn2)c1
Agent: CC(C)(C)C(=O)O
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CCC(O)(c1ncc(-c2cc(C)cc(Nc3cc(C4CC4)ccn3)n2)s1)[C@H]1CC[C@H](C(=O)OC)CC1
Temperature: 100 °C

Procedure:
6-Bromo-N-(4-cyclopropylpyridin-2-yl)-4-methylpyridin-2-amine (263 mg, 0.865 mmol), trans-methyl 4-[1-hydroxy-1-(1,3-thiazol-2-yl)propyl]cyclohexanecarboxylate (245 mg, 0.865 mmol), pivalic acid (151 μl, 1.297 mmol), potassium carbonate (358 mg, 2.59 mmol), π-allyl palladium(II)chloride dimer (31.6 mg, 0.086 mmol) and butyl di-1-adamantylphosphine (124 mg, 0.346 mmol) were combined and the reaction flask was put under inert atmosphere (3× vacuum/argon cycle) then degassed dimethylacetamide (2 mL) was added. The reaction was heated to 100° C. for 5 hours, then cooled to room temperature and poured into diethyl ether (100 mL). The resulting solution was transferred to a separatory funnel and sequentially washed with water (3×50 mL) and sodium bicarbonate (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude oil was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to afford methyl trans-4-[l-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylate as a yellow foam. MS ESI calc'd. for C28H35N4O3S [M+H]+ 507. found 507. 1H NMR (500 MHz, CDCl3) δ 8.12-8.04 (m, 2H), 7.71 (s, 1H), 7.23 (s, 1H), 7.05 (s, 1H), 6.86 (s, 1H), 6.66 (d, J=5.2 Hz, 1H), 3.64 (s, 3H), 2.35 (s, 3H), 2.28-2.16 (m, 1H), 2.16-1.86 (m, 811), 1.51-1.30 (m, 3H), 1.26 (t, J=7.1 Hz, 1H), 1.21-1.06 (m, 3H), 1.03-0.93 (m, 2H), 0.83 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][C:20]#[N:21]>>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[C:20]([NH2:21])=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][N:5]=[CH:4][CH:3]=2
Reactant: Nc1ccncc1C=O
Reactant: COc1ccccc1CCC#N
Product: COc1ccccc1Cc1cc2cnccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 4-aminonicotinaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:46])[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:42]([CH3:45])[CH2:43][CH3:44])[C@H:35]([O:40][CH3:41])[CH2:36][C:37](O)=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:48][O:49][C@@H:50]([C@@H:68]1[CH2:72][CH2:71][CH2:70][NH:69]1)[C@@H:51]([CH3:67])[C:52]([NH:54][C@H:55]([C:63]([O:65][CH3:66])=[O:64])[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[S:53].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O.ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:46])[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:42]([CH3:45])[CH2:43][CH3:44])[C@H:35]([O:40][CH3:41])[CH2:36][C:37]([N:69]3[CH2:70][CH2:71][CH2:72][C@H:68]3[C@H:50]([O:49][CH3:48])[C@@H:51]([CH3:67])[C:52]([NH:54][C@@H:55]([CH2:56][C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C:63]([O:65][CH3:66])=[O:64])=[S:53])=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=S)[C@H](C)[C@@H](OC)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure D, from #8 (247 mg, 0.387 mmol, 1 eq.), #39 (186 mg, ≦0.450 mmol, 1.2 eq.), dichloromethane (10 mL, 0.04 M), N,N-dimethylformamide (2 mL), HATU (176 mg, 0.464 mmol, 1.2 eq.) and triethylamine (189 mL, 1.35 mmol, 3.5 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 25% acetone in heptane) to give #40 (410 mg, 90% over 2 steps) as an off-white solid. LC-MS: m/z 984.7 [M+H+], 1006.7 [M+Na+], retention time=1.15 minutes; HPLC (Protocol C): retention time=9.683 minutes (purity >99%); 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.19 (br d, J=7 Hz) and 10.49 (br d, J=8 Hz), total 1H], 7.90 (d, J=7.5 Hz, 2H), 7.60-7.65 (m, 2H), 7.38-7.45 (m, 2H), 7.29-7.35 (m, 2H), 7.14-7.28 (m, 5H), [5.20 (ddd, J=11, 7, 4 Hz) and 5.35-5.43 (m), total 1H], 3.65 and 3.69 (2 s, total 3H), [1.15 (d, J=6.5 Hz) and 1.18 (d, J=6.4 Hz), total 3H].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25](/[CH:27]=[C:28](/[P:30](=[O:37])([O:34]CC)[O:31]CC)\[F:29])=[CH:26][C:4]=2[N:3]=1.C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25](/[CH:27]=[C:28](/[P:30](=[O:31])([OH:34])[OH:37])\[F:29])=[CH:26][C:4]=2[N:3]=1
Reactant: CCOP(=O)(OCC)/C(F)=C/c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COc1ccc(CCc2cnc3c(N)nc4cc(/C=C(\F)P(=O)(O)O)ccc4c3c2)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of (E)-diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinylphosphonate (3-2) (1.0 equiv.) in DCM (0.05 M) at 0° C. was added TMSBr (10 equiv.). The reaction was warmed to room temperature over 2 hours, and then quenched with small amounts of MeOH. The DCM was removed by evaporation, and then DMSO/water was added. The mixture was adjusted to pH 9 and directly purified on RP-HPLC using a C18 column, eluting with 10-40% 95:5 (MeCN/5 mM NH4OAc) in 10 mM NH4OAc (pH 9) gradient. The fractions containing the product were combined and concentrated in vacuo to give (E)-2-(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinylphosphonic acid (12) as a solid. 1H NMR (Dimethylsulfoxide-d6): δ 9.80 (s, 1H), 9.41 (s, 1H), 9.05 (s, 1H), 8.87 (s, 1H), 8.65 (d, 1H, J=8.8 Hz), 8.08 (s, 1H), 7.76 (d, 1H, J=8.4 Hz), 7.08 (d, 1H, J=8.4 Hz), 7.02 (d, 1H, J=8.4 Hz), 6.83-6.65 (m, 2H), 3.69 (s, 3H), 3.18-3.12 (m, 2H), 3.02-2.96 (m, 4H), 2.28 (s, 3H). LRMS [M+H]=468.1
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]([NH2:27])=[N:24][N:23]=2)=[CH:18][CH:17]=1.[CH2:28]([NH:30][S:31]([C:34]1[CH:35]=[C:36]([F:44])[C:37]([F:43])=[C:38]([CH:42]=1)[C:39](O)=[O:40])(=[O:33])=[O:32])[CH3:29].CN(C=O)C>>[CH2:28]([NH:30][S:31]([C:34]1[CH:35]=[C:36]([F:44])[C:37]([F:43])=[C:38]([CH:42]=1)[C:39]([NH:27][C:25]1[S:26][C:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)=[N:23][N:24]=1)=[O:40])(=[O:33])=[O:32])[CH3:29]
Reactant: CCNS(=O)(=O)c1cc(F)c(F)c(C(=O)O)c1
Reactant: Nc1nnc(-c2ccc(F)cc2)s1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCNS(=O)(=O)c1cc(F)c(F)c(C(=O)Nc2nnc(-c3ccc(F)cc3)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a 20 ml scintillation vial was added EDC (54 mg, 0.283 mmol), HOAt (38 mg, 0.283 mmol) and commercially available 5-(4-fluorophenyl)-1,3,4-thiadiazol-2-amine (55 mg, 0.283 mmol). To this was added 5-[(ethylamino)sulfonyl]-2,3-difluorobenzoic acid as a solution in 2 ml DMF (75 mg, 0.283 mmol based on theoretical yield of preceding). The reaction mixture was stirred at room temperature overnight with a Teflon covered magnetic stir-bar. The reaction mixture was then concentrated to ˜1 ml and the residue was purified using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 30% B to 60% B in 10 min, where A=H2O and B=CH3CN pumped at 150 mL/min to yield 5-[(Ethylamino)sulfonyl]-2,3-difluoro-N-[5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl]benzamide as a white solid (12 mg, 19%).
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][C:14]1[C:19]([CH2:20][OH:21])=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[C:16]([CH3:28])[N:15]=1>C(Cl)Cl>[CH3:8][S:9]([O:21][CH2:20][C:19]1[C:14]([CH3:13])=[N:15][C:16]([CH3:28])=[CH:17][C:18]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(-c2ccccc2)c(CO)c(C)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccccc2)c(COS(C)(=O)=O)c(C)n1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
NEt3 (0.60 mL, 4.31 mmol) and methanesulphonyl chloride (0.20 mL, 2.59 mmol) were added to a solution of (2,6-dimethyl-4-phenylpyridin-3-yl)methanol (460 mg, 2.16 mmol) in DCM (40 mL) at 0° C. After stirring for 40 min at 0° C. the reaction mixture was diluted with DCM, washed with sat. aqueous NaHCO3 solution, water and dried (MgSO4). Removal of the solvent provided crude (2,6-dimethyl-4-phenylpyridin-3-yl)methyl methanesulfonate which was used without further purification (650 mg).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([OH:14])=O.ClC(OCC(C)C)=O.[CH2:26]([SH:28])[CH3:27]>ClCCl.O>[Br:8][C:9]1[CH:10]=[C:11]([C:12](=[O:14])[S:28][CH2:26][CH3:27])[CH:15]=[CH:16][N:17]=1
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: CCS
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCSC(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
Triethylamine (3.0 g, 29.7 mmol) was added to a suspension of 2-bromo-isonicotinic acid (5.0 g, 24.8 mmol) in anhydrous dichloromethane (50 mL). The mixture was stirred at room temperature for 10 minutes, cooled to 0° C. and isobutyl chloroformate (3.6 g, 26.0 mmol) was added dropwise. The reaction mixture was then stirred at 0° C. for 30 minutes, ethanethiol (1.6 g, 25.99 mmol) was then added dropwise and the stirring was continued for an additional 2 h at 0° C. The reaction mixture was diluted with dichloromethane (100 mL) and water (100 mL). The organic layer was separated, washed with water, dried over is sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in hexane to afford the title compound (5.0 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>CCO.Cl.[Fe]>[Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[CH:4][C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1
Reactant: Nc1cc(Cl)c(-c2ccc(-c3ccccc3)cc2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cc(Cl)c(-c2ccc(-c3ccccc3)cc2)cc1N
Temperature: 130 °C

Procedure:
A 5 mL Biotage™ microwave vial was charged with Fe (285.0 mg, 5.11 mmol), a solution of compound 2-1 (166.0 mg, 0.511 mmol) in EtOH (3 mL) and diluted aqueous HCl (82 uL of 37% aqueous HCl, diluted with 0.75 mL of water). The resulting suspension was heated in a microwave synthesizer (Biotage Initiator™) at 130° C. for 10 min. The mixture was then filtered and the remaining solids were washed with EtOAc (three times, 2 mL). The filtrate and washes were combined and evaporated to dryness in vacuo. The residue was dissolved in 3:1 EtOAc/TEA and passed through a short plug of a neutral alumina. The resulting solution was evaporated to dryness in vacuo to give the crude product as brownish oil. LR-MS (API-ES): calculated for C18H15ClN2 294.1, observed m/e 295.0 (M+H)+ (Rt 3.07 min). The crude product was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[N:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[H-].[Na+]>CN(C)C=O>[CH2:28]([N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[N:21]=1)[S:16]([C:13]1[CH:14]=[CH:15][C:10]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH:29]([CH3:31])[CH3:30]
Reactant: OCc1ccncc1
Reactant: COc1cccc(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3ccncc3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.8 %

Procedure:
Pyridin-4-ylmethanol (20.22 mg, 0.185 mmol) and 4-fluoro-N-isobutyl-N-(6-methoxypyridin-2-yl)benzenesulfonamide (62.7 mg, 0.185 mmol) were dissolved in N,N-dimethylformamide (DMF) (3 mL) and sodium hydride (7.41 mg, 0.185 mmol, 60% wt in mineral oil) added. Reaction left to stir at room temperature, under nitrogen, for 3 hours. The reaction was then quenched by adding water (2 mL). The mixture was concentrated in vacuo and the product extracted to the organic phase of an aqueous work up between ethyl acetate and water. The organic phase was dried by passing it through a hydrophobic frit, concentrated and then purified by mass directed autoprep (formic acid modifier), to give the title compound (21.2 mg). LCMS (2 min, formic) Rt 1.05 min, m/z (ES+) 428 (M+H).
Reaction SMILES: [C:1]1([C:7]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][C:14]([CH3:27])=[N:13]4)[NH:10][C:9]([CH3:32])(S(O)(=O)=O)[C:8]=2S(O)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na][Na]>>[C:1]1([C:7]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][C:14]([CH3:27])=[N:13]4)[N:10]=[C:9]([CH3:32])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(-c2ccccc2)c2ccc3c(c2n1)NC(C)(S(=O)(=O)O)C(S(=O)(=O)O)=C3c1ccccc1
Agent: [Na][Na]
Product: Cc1cc(-c2ccccc2)c2ccc3c(-c4ccccc4)cc(C)nc3c2n1

Procedure:
4, 7-Diphenyl-2, 9-dimethyl-1, 10-phenanthrolinedisulfonic acid, disodium salt
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][C@H:16]([NH:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.C(=O)(O)[O-:36].[Na+]>C(O)(C)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][C@H:16]([NH:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH3:17])=[CH:10][C:11]=2[C:13]([NH2:14])=[O:36])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CC(=O)N1CCc2cc(C[C@@H](C)NCCOc3ccccc3OCC(F)(F)F)cc(C#N)c21
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)N1CCc2cc(C[C@@H](C)NCCOc3ccccc3OCC(F)(F)F)cc(C(N)=O)c21

Procedure:
To a solution of (R)-(-)-1-acetyl-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carbonitrile (2.00 g) in isopropanol (4.2 ml) was added concentrated hydrochloric acid (4.2 ml) slowly with stirring under ice cooling, and the mixture was stirred for 40 minutes. The reaction mixture was neutralized by a saturated aqueous sodium bicarbonate solution, and extracted with methylene chloride. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 1.70 g of (R)-(-)-1-acetyl-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carboxamide melting at 144°-146° C.