Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.[CH3:34][S:35]([O-:37])=[O:36].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.ClCCl>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([S:35]([CH3:34])(=[O:37])=[O:36])=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(S(C)(=O)=O)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A mixture of 369 mg (0.758 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide (Example 2) and 176 mg (1.67 mmol) sodium methanesulfinate in 4 ml N,N-dimethylformamide was heated at reflux over night. After cooling to room temperature the mixture was diluted with dichloromethane and treated with saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with three portions of dichloromethane. The combined organic layers were dried with sodium sulfate, concentrated and and dried in high vacuo. Flash column chromatography gave 118 mg (29%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[O:39]=[S:40]1(=[O:49])[CH2:45][CH2:44][N:43]([CH2:46][CH2:47]O)[CH2:42][CH2:41]1>>[Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:47][CH2:46][N:43]1[CH2:44][CH2:45][S:40](=[O:49])(=[O:39])[CH2:41][CH2:42]1)[CH:5]=2
Reactant: O=S1(=O)CCN(CCO)CC1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Reaction time: 2 h
Yield: 29 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 36 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(1,1-dioxothiomorpholin-4-yl)ethanol instead of 4-(2-hydroxyethyl)morpholine, being stirred for 2 h to obtain the title compound (29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][NH:11][C:12]([CH:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15]2)=O)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C([O-])=O.[NH4+:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:35]=[C:12]([CH:14]3[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15]3)[NH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [NH4+]
Reactant: COc1cccc(C(=O)CNC(=O)C2CN(Cc3ccccc3)CCO2)c1
Agent: O=C([O-])C(F)(F)F
Product: COc1cccc(-c2c[nH]c(C3CN(Cc4ccccc4)CCO3)n2)c1
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 102.9 %

Procedure:
A mixture of N-{2-[3-(methyloxy)phenyl]-2-oxoethyl}-4-(phenylmethyl)-2-morpholinecarboxamide (1.6 g, 4.34 mmol) and ammonium trifluoroacetate (2.85 g, 21.71 mmol) was stirred for 0.75 hours at 150° C. The LCMS indicated that the starting material was consumed. The desired product was contained in the residue. Water (50 mL) was added to the residue, and the resulting mixture was extracted with EtOAc (3×50 mL). The organics were dried (Na2SO4), filtered, and concentrated to afford the title compound (1.56 g) as a brown oil. LC-MS (ES) m/z=350 [M+H]+.
Reaction SMILES: CN(C)S([N:6]1[C:10]2=[C:11]3[C:16](=[CH:17][CH:18]=[C:9]2[CH:8]=[N:7]1)[C:15](=[O:19])[C:14]([I:20])=[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:12]3)(=O)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:20][C:14]1[C:15](=[O:19])[C:16]2[C:11]([O:12][C:13]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:10]1[NH:6][N:7]=[CH:8][C:9]1=[CH:18][CH:17]=2
Reactant: CN(C)S(=O)(=O)n1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cn[nH]c12
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of 7-iodo-6-oxo-8-phenyl-6H-9-oxa-1,2-diaza-cyclopenta[a]naphthalene-1-sulfonic acid dimethylamide (82 mg, 0.166 mmol) in DCM (2 mL) was added TFA (0.5 mL) at RT. After 3 h, the reaction mixture was concentrated in vacuo to afford the title compound as a white solid (64 mg, 100%). LCMS (Method A): RT=4.23 min, [M+H]+=389.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[C:26]([O:27][CH3:28])[CH:25]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(B(O)O)cc1OC
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)c(OC)c3)cccc2c1N
Yield: 75.3 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 3,4-dimethoxyphenyl boronic acid (148 mg, 0.97 mmol) were reacted to afford the title compound (91 mg, 77.7% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.58 (br, 1H), 7.76-7.88 (m, 2H), 7.71 (t, J=7.7 Hz, 1H), 7.29 (m, overlapped with CHCl3), 7.23 (d, J=1.9 Hz, 1H), 7.02 (d, J =8.3 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.47 (q, J=6.7 Hz, 2H), 1.68 (m, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=367 (M+H) HPLC 1.78 min.
Reaction SMILES: C([O:4][C@@H:5]([CH3:38])/[CH:6]=[CH:7]\[C:8]([NH:10][C@H:11]1[C@@H:16]([CH3:17])[O:15][C@@H:14]([CH2:18]/[CH:19]=[C:20](\[CH3:36])/[CH:21]=[CH:22]/[C@@H:23]2[CH2:30][C@@:27]3([O:29][CH2:28]3)[CH2:26][C@@H:25]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[O:24]2)[C@@H:13]([CH3:37])[CH2:12]1)=[O:9])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][C@@H:5]([CH3:38])/[CH:6]=[CH:7]\[C:8]([NH:10][C@H:11]1[C@@H:16]([CH3:17])[O:15][C@@H:14]([CH2:18]/[CH:19]=[C:20](\[CH3:36])/[CH:21]=[CH:22]/[C@@H:23]2[CH2:30][C@@:27]3([O:29][CH2:28]3)[CH2:26][C@@H:25]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[O:24]2)[C@@H:13]([CH3:37])[CH2:12]1)=[O:9]
Reactant: COC(=O)C[C@@H]1C[C@@]2(CO2)C[C@@H](/C=C/C(C)=C/C[C@@H]2O[C@H](C)[C@H](NC(=O)/C=C\[C@H](C)OC(C)=O)C[C@@H]2C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C[C@@H]1C[C@@]2(CO2)C[C@@H](/C=C/C(C)=C/C[C@@H]2O[C@H](C)[C@H](NC(=O)/C=C\[C@H](C)O)C[C@@H]2C)O1
Reaction time: 2 h

Procedure:
Synthesis of methyl [(3S,5S,7S)-7-{(1E,3E)-5-[(2S,3S,5R,6R)-5-{[(2Z,4S)-4-hydroxypent-2-enoyl]amino}-3,6-dimethyltetrahydro-2H-pyran-2-yl]-3-methylpenta-1,3-dien-1-yl}-1,6-dioxaspiro[2.5]oct-5-yl]acetate (#B148). To a solution of the crude material from Step 1 of example A#50 in methanol (3.5 mL) at rt was added potassium carbonate (136 mg, 0.056 mmol, 2.5 eq.), and the reaction was stirred for 2 hours. The reaction was filtered with methanol, diluted with dimethyl sulfoxide (2 mL), and concentrated in vacuo. Purification by reverse phase medium pressure liquid chromatography eluted with 0.02% acetic acid in water (v/v) and 0.02% acetic acid in acetonitrile (v/v) (10% to 90%) provided #B148 as a white solid. Yield: 91.6 mg, 0.18 mmol, 48%. LCMS (Protocol D): m/z 492.47 [M+H]+, retention time=0.80 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J=7.8 Hz, 1H), 6.25 (d, J=16.0 Hz, 1H), 5.97 (d, J=11.9 Hz, 1H), 5.87 (d, J=11.9 and 7.0 Hz, 1H), 5.65-5.48 (m, 2H), 5.22-5.13 (m, 1H), 5.10 (d, J=4.7 Hz, 1H), 4.56-4.48 (m, 1H), 4.36-4.25 (m, 1H), 3.69-3.61 (m, 2H), 3.60 (s, 3H), 3.55-3.46 (m, 1H), 2.74-2.56 (m, 4H), 2.38-2.13 (m, 2H), 1.90-1.60 (m, 9H), 1.44 (dd, J=13.2 and 7.0 Hz, 1H), 1.11 (d, J=6.2 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H), 0.96 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:28][CH3:29])[CH:8]=[C:9]([C:12]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)O)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:9]2[CH:10]=[C:11]3[C:6](=[C:7]([O:28][CH3:29])[CH:8]=2)[N:5]=[CH:4][CH:3]=[C:2]3[Br:1])=[CH:26][CH:25]=1
Reactant: COc1cc(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc2c(Br)ccnc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc2c(Br)ccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed (4-bromo-8-methoxyquinolin-6-yl)bis(4-chlorophenyl)methanol (6 g, 12.27 mmol, 1.00 equip), dichloromethane (200 mL), triethylsilane (8 mL), and trifluoroacetic acid (24 mL). The resulting solution was stirred overnight at 25° C. The resulting solution was diluted with DCM (100 mL). The resulting mixture was washed with saturated sodium bicarbonate (3×100 mL) and dried over anhydrous sodium sulfate. The solids were filtered out. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:1) to yield 6-[bis(4-chlorophenyl)methyl]-4-bromo-8-methoxyquinoline as a yellow solid. LCMS (ES, m/z) 474 [M+H]+
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])/[C:7](/[NH:16][C:17](=[O:36])[C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[O:25])=[CH:20][C:19]=1[Cl:35])=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1>O.O1CCCC1.CO.O>[Br:15][C:12]1[CH:13]=[CH:14][C:9](/[CH:8]=[C:7](\[NH:16][C:17](=[O:36])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=3)=[O:25])=[CH:20][C:19]=2[Cl:35])/[C:6]([OH:37])=[O:5])=[CH:10][CH:11]=1
Reactant: COC(=O)/C(=C/c1ccc(Br)cc1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C(=C/c1ccc(Br)cc1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.9 %

Procedure:
A solution of lithium hydroxide monohydrate (10.6 mg, 0.25 mmol) in water (1 mL) was added to a solution of (Z)-3-(4-bromophenyl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid methyl ester (Example 224; 69 mg, 0.13 mmol) in tetrahydrofuran/methanol/water (3:1:1; 1.5 ml). The mixture was stirred for 4 h at room temperature and then acidified. The product was filtered off and purified by HPLC (Waters system) to give (Z)-3-(4-bromophenyl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid (33 mg, 49% yield).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([CH3:19])[C:10]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:10]1[C:9]([CH3:19])=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)Nc1onc(C)c1Br
Yield: 88 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2-toluenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2-toluenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give white crystalline solid, m.p. 93-96° C., yield 88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl>[Zn].Cl[Hg]Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)CCCC(=O)O)cc1OC
Agent: Cl
Agent: Cl[Hg]Cl
Agent: [Zn]
Product: COc1ccc(CCCCC(=O)O)cc1OC

Procedure:
A mixture containing 37.6 g of the product obtained in Example 38 and 64 g of zinc turnings (treated with a solution of HgCl2), 55 ml of tolueneand 220 ml of cone. hydrochloric acid was refluxed for 1 h. Toluene phase was separated and evaporated in vacuo. The residue was crystallized from toluene-petroleum ether, yield 11.5 g (32%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[S:27].C(O)(=O)C.N1CCCCC1.C1(C)C=CC=CC=1>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][C:10]=1[CH:11]=[C:31]1[S:25][C:26](=[S:27])[NH:28][C:29]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1cc(OCc2ccccc2)ccc1OCc1ccccc1
Reaction time: 1.5 h

Procedure:
1.59 g (5 mmol) of 2,5-bis-benzyloxybenzaldehyde, 0.73 g (5.5 mmol) of rhodanine, 0.29 g (2 mmol) of piperidine acetate and 40 ml of toluene were heated on a water separator under a nitrogen atmosphere for 1.5 hours. After cooling, the yellow crystals were filtered off under suction, washed with toluene and diethyl ether and dried in a vacuum: 1.34 g (62%) of 5-[(2,5-bis-benzyloxyphenyl)methylene]-4-oxo-2-thioxo-thiazolidine; 1HNMR (DMSO-d6, 250 MHz) δ 13.80 (s, 1H), 7.80 (s, 1H), 6.85-7.50 (m, 13H), 5.19 (s, 2H), 5.10 (s, 2H); TLC (toluene/methyl ethyl ketone/glacial acetic acid (72:20:8)): Rf=0.80.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1([CH3:40])[O:17][N:16]=[C:15]([S:18][CH:19]([C:24]2[C:25]([C:36]([F:39])([F:38])[F:37])=[N:26][N:27]([CH3:35])[C:28]=2[O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[C:20]([F:23])([F:22])[F:21])[CH2:14]1>ClCCl>[CH3:12][C:13]1([CH3:40])[O:17][N:16]=[C:15]([S:18]([CH:19]([C:24]2[C:25]([C:36]([F:39])([F:37])[F:38])=[N:26][N:27]([CH3:35])[C:28]=2[O:29][CH2:30][C:31]([F:32])([F:33])[F:34])[C:20]([F:23])([F:22])[F:21])=[O:6])[CH2:14]1
Reactant: Cn1nc(C(F)(F)F)c(C(SC2=NOC(C)(C)C2)C(F)(F)F)c1OCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1nc(C(F)(F)F)c(C(S(=O)C2=NOC(C)(C)C2)C(F)(F)F)c1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
3-Chloroperoxybenzoic acid (mCPBA) (70% by weight) (305 mg, 1.24 mmol) was added in portions to a solution of 5,5-dimethyl-3-{2,2,2-trifluoro-1-[1-methyl-5-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethylsulfanyl}-4,5-dihydro-isoxazole (190 mg, 0.41 mmol) in dichloromethane (5 ml) at room temperature. The mixture was stirred at room temperature for 18 hours. The reaction was quenched by addition of saturated aqueous sodium metabisulfite solution, followed by addition of saturated aqueous sodium hydrogencarbonate solution. The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: hexane/dichloromethane) to give the product (Compound No. 2.35 of Table 28) as a colourless gum (105 mg, 51% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[CH2:8]1
Reactant: Cc1ccnc2c1C(=O)CC(c1sccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1sccc1Cl)C2
Yield: 115 %

Procedure:
A mixture of 7-(3-chloro-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.3 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.27 ml), water (0.27 ml) and ethanol (30 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The mixture was washed with ethyl acetate, and to the mixture was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added a solution of 4N hydrochloric acid-ethyl acetate (0.4 ml), and the mixture was concentrated under reduced pressure. The resulting crystals were recrystallized from ethanol-water to give 7-(3-chloro-2-thienyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 74) (0.23 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[F:20][C:21]([F:33])([F:32])[O:22]C1C=CC=C2C=1NC=C2>>[F:20][C:21]([F:33])([F:32])[O:22][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: FC(F)(F)Oc1cccc2cc[nH]c12
Product: CC1(C)OB(c2cc3cccc(OC(F)(F)F)c3[nH]2)OC1(C)C

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-trifluoromethoxy-1H-indole.
Reaction SMILES: C[Al](C)C.[CH3:5][S:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.[Si:14]([O:21][C@@H:22]([CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:23](OC)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.CCOC(C)=O>[Si:14]([O:21][C@@H:22]([CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([S:6][CH3:5])=[CH:12][N:11]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CSc1ccc(N)nc1
Reactant: COC(=O)[C@H](COC(C)C)O[Si](C)(C)C(C)(C)C
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CSc1ccc(NC(=O)[C@H](COC(C)C)O[Si](C)(C)C(C)(C)C)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.8 %

Procedure:
Trimethylaluminium (2M in toluene) (10.40 mL, 20.80 mmol) was added to 5-(methylthio)pyridin-2-amine (CAS no. 77618-99-6) (2.54 g, 18.09 mmol) in toluene (100 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-methyl 2-(tert-butyldimethylsilyloxy)-3-isopropoxypropanoate (Intermediate C7b) (5 g, 18.09 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was allowed to stir at room temperature for 1 hour. The temperature was increased to 60° C. and stirred for a further 24 hours. The reaction mixture was neutralised with citric acid (1M, aq) and then diluted with water and EtOAc (200 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (100 mL). The combined organics were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% Et2O in isohexane to afford the product (3.95 g, 56.8%). 1H NMR (400 MHz, DMSO) δ 0.10-0.13 (6H, d), 0.90-0.92 (9H, m), 1.04-1.07 (6H, m), 2.40 (3H +DMSO, s), 3.54-3.63 (3H, m), 4.42-4.44 (1H, m), 7.77-7.80 (1H, dd), 8.03-8.06 (1H, d), 8.26 (1H, d), 9.49 (1H, s); m/z (ES+) (M+H)+=385; HPLC tR=3.66 min.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[I:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH3:27])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[I:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH3:27])=[CH:22][CH:21]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(NC1CC1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
Cyclopropylamine (0.85 g), acetic acid (0.89 g), and sodium triacetoxyborohydride (3.2 g) were added to a chloroform (20 mL) solution of 1-(4-iodophenyl)ethanone (1.2 g), and the mixture was stirred in a nitrogen atmosphere for 24 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and then the mixture was extracted with chloroform. Then, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (hexane/ethyl acetate=80/20) to obtain N-[1-(4-iodophenyl)ethyl]cyclopropylamine (colorless oil) (1.3 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([I:18])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=[O:17].C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][OH:28].O>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([I:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:26][CH2:27][OH:28])[CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=[O:17]
Reactant: OCCI
Reactant: CCOC(=O)c1c[nH]c2c(F)cc(I)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCO)c2c(F)cc(I)cc2c1=O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Ethyl 8-fluoro-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 11, 7.22 g, 20 mmol) was dissolved in dimethylformamide (35 ml). Powdered potassium carbonate (8.28 g, 60 mmol) and 2-iodoethanol (11.3 ml, 145 mmol) were then added and the reaction mixture was allowed to stir at 90° C. for 1 h. The reaction mixture was cooled to room temperature and poured into brine (300 ml) then water (50 ml) was added to dissolve the material. This solution was extracted with 9:1 tetrahydrofuran:methyl tert-butyl ether (5×200 ml). The organic extracts were combined washed with brine (2×200 ml), dried over sodium sulfate, and concentrated under reduced pressure to give a dark yellow oil of ethyl 8-fluoro-1-(2-hydroxyethyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate that was carried on to the next reaction without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([OH:40])=O)([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C[NH:59][S:60]([CH:63]1[CH2:65][CH2:64]1)(=[O:62])=[O:61].C1CCN2C(=NCCC2)CC1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([NH:59][S:60]([CH:63]([CH3:65])[CH3:64])(=[O:62])=[O:61])=[O:40])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3cccc(F)c3)nc2c1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C(C)C)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3cccc(F)c3)nc2c1C
Temperature: 50 °C
Reaction time: 18 h
Yield: 36.1 %

Procedure:
A mixture of the acid 159 (71 mg, 0.115 mmol) and CDI (37 mg, 0.228 mmol) in dry THF (10 mL) was heated at reflux for 2 h under N2. The reaction mixture was cooled 50° C. and a pre-mixed solution of methyl-cyclopropyl sulfonamide (43 mg, 0.349 mmol) and DBU (49 μL, 0.322 mmol) in 2 ml of dry THF was added to the reaction mixture. The reaction was stirred at 50° C. for 18 h. The solvent was evaporated and the residue was dissolved in CHCl3 and washed with citric acid (10% aq). The organic phase was dried with Na2SO4, filtered and the solvent was removed by rotary evaporation. The crude product was purified by HPLC on an Ace-5 C8 column (100×21.2 mm) with a gradient going from 35 to 60% acetonitrile (0.1% TFA) in H2O (0.1% TFA) over 8 minutes. The product was obtained as a white solid (30 mg, 36%), LRMS (M+H) 722.