Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@@H:13]([OH:25])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl:26][C:27]1[CH:32]=[C:31](Cl)[N:30]=[CH:29][N:28]=1>C1COCC1>[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:14][C@@H:13]([O:25][C:31]2[CH:32]=[C:27]([Cl:26])[N:28]=[CH:29][N:30]=2)[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 112.5 %

Procedure:
To a suspension of sodium hydride (75.6 mg, 0.00189 mol) in THF (2 mL) at 0° C. under an atmosphere of nitrogen was added (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol (0.60 g, 0.0017 mol) in 1.5 mL THF dropwise at 0° C. The mixture was stirred at 0° C. for 10 min. To this was next added 4,6-dichloro-pyrimidine (0.225 g, 0.00151 mol) in 2 mL THF at 0° C. The suspension was stirred at 0° C. for 2 hrs. The reaction was quenched with 9 mL saturated aqueous NH4Cl and extracted with t-BuOMe (3×). The organic layers were combined and washed with brine, dried over anhydrous MgSO4 and then concentrated to give 0.804 g of an oil. The residue was purified by flash chromatography (0 to 10% EtOAc/hexanes) to give 0.63 g (80%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]=[CH:12][N:13](C)C)[C:8]([C:16]#[N:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:43])[C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:30][CH:29]=2)=[C:23](N)[CH:22]=1.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>CC(O)=O.O>[CH3:18][O:19][C:20](=[O:43])[C:21]1[CH:22]=[CH:23][C:24]([S:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[CH:30][CH:29]=2)=[C:25]([NH:17][C:16]2[C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[N:10][C:9]=3[N:11]=[CH:12][N:13]=2)[CH:26]=1
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Reactant: CN(C)C=Nc1nc(C(C)(C)C)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)(C)C)ccc23)c1
Temperature: 120 °C
Yield: 47.3 %

Procedure:
A suspension of N′-(6-tert-butyl-3-cyano-pyridin-2-yl)-N,N-dimethyl-formamidine (0.46 g, 2.0 mmol) and 3-amino-4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-benzoic acid methyl ester [prepared in Example 385C] (0.75 g, 2.0 mmol) in AcOH (10 mL) was heated at 120° C. for 30 minutes under N2. After cooling to room temperature, the reaction mixture was portioned between AcOEt and H2O, and then made basic to pH 9 with K2CO3 under stirring. The organic layer was separated, washed with 10% NaHCO3, H2O and brine, dried over MgSO4, and evaporated to give pale brown oil. The oily residue was separated by silica gel column chromatography (CH2Cl2/MeOH=98/2) to give the title compound as off-white powder (0.53 g, 47%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17]([C:19]1[N:20]([CH2:33][CH2:34][CH2:35][C:36]#[CH:37])[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:31])[C:22]=2[N:32]=1)[CH3:18]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[IH:1].[CH2:17]([C:19]1[N:20]([CH2:33][CH2:34][CH2:35][C:36]#[C:37][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:31])[C:22]=2[N:32]=1)[CH3:18]
Reactant: C#CCCCn1c(CC)nc2c(N)nc3ccccc3c21
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCC#Cc1ccc(OC)cc1
Product: I
Reaction time: 4 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.095 g, 0.03 eq.), 4-iodoanisole (0.786 g, 1.1 eq.), triethylamine (1.3 mL, 3 eq.), and copper (I) iodide (0.035 g, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(4-pentynyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.85 g, 3.0 mmol, 1.0 eq.) in DMF. The reaction mixture was stirred for about 4 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 4/96 methanol/dichloromethane) to provide an oil. The oil was recrystallized from ethanol to provide 2-ethyl-1-[5-(4-methoxyphenyl)-4-pentynyl]-1H-imidazo[4,5-c]quinolin-4-amine hydroiodide as off white granules, mp 230.0° C. 1H NMR (300 MHz, DMSO-d6) δ 13.14 (broad s, 1H), 8.65 (broad s, 2H), 8.37 (d, J=8.6 Hz, 1H), 7.83 (dd, J=8.4, 0.8 Hz, 1H), 7.68 (t, J=7.4 Hz, 1H), 7.41 (dt, J=8.1, 0.7 Hz, 1H), 7.34 (m, 2H), 6.93 (m, 2H), 4.73 (t, J=7.5 Hz, 2H), 3.77 (s, 3H), 3.08 (q, J=7.4 Hz, 2H), 2.66 (t, J=6.9 Hz, 2H), 2.09 (m, 2H), 1.41 (t, J=7.4 Hz, 3H); MS (APCI) m/z 385 (M+H)+; Anal. calcd for C24H24N4O1.HI.0.08C2H4Cl2: C, 55.30; H, 4.89; N, 10.69. Found: C, 55.39; H, 4.88; N, 10.63.
Reaction SMILES: O[C:2](=[C:7]1[C:11]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]1=O)[CH2:3][CH2:4]CC.S(=O)(=O)(O)O.[C:25]([OH:28])(=[O:27])[CH3:26]>>[CH2:7]([C:8]1[O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:26]=1[C:25]([OH:28])=[O:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(O)=C1C(=O)Oc2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)O

Procedure:
263 g of 3-(1-hydroxypentylidene)-5-nitro-3H-benzofuran-2-one, 480 g of acetic acid and 190 g of 90% concentrated sulphuric acid are charged to a three-necked round-bottomed flask.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][N:5]1[CH2:9][C:8]([OH:10])=[C:7]([C:11]2[CH2:15][N:14]([CH2:16][C:17]([O:19]C)=[O:18])[C:13](=[O:21])[CH:12]=2)[C:6]1=[O:22].[OH-].[Na+].Cl>O>[OH:10][C:8]1[CH2:9][N:5]([CH2:4][C:3]([OH:23])=[O:2])[C:6](=[O:22])[C:7]=1[C:11]1[CH2:15][N:14]([CH2:16][C:17]([OH:19])=[O:18])[C:13](=[O:21])[CH:12]=1
Reactant: COC(=O)CN1CC(C2=C(O)CN(CC(=O)OC)C2=O)=CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CC(C2=C(O)CN(CC(=O)O)C2=O)=CC1=O
Reaction time: 2 h

Procedure:
6.5 g (0.02 mol) of 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid dimethyl ester are stirred in 100 ml of water and 20 ml of concentrated aqueous sodium hydroxide solution for 12 hours at 90°. The solution is then rendered strongly acidic with concentrated aqueous hydrochloric acid solution while cooling with an ice-water bath. The resulting suspension is stirred for a further 2 hours in order to complete the reaction, then filtered, washed with water and acetone and dried under a high vacuum. 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid is obtained in the form of white microcrystals having a melting point of 268° (decomposition).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])=[CH:12]2.CN(C)C=O.ClCCl.Cl>C(OCC)(=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:22](=[O:23])[CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=3)=[O:19])[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
4-Hydroxypiperidine (0.83 mmol) and [(5-chloro-1H-indole-2-carbonyl)-amino]-acetic acid (0.8 mmol) were coupled according to procedure A (dimethylformamide-dichloromethane reaction solvent) with the following workup: the reaction mixture was stirred with ethyl acetate and aqueous 2 N HCl, the resulting suspension filtered and the collected solid washed successively with aqueous 2 N HCl, aqueous 2 N NaOH, ether and dried: Yield 180 mg, 68%; TSPMS 336/338 (MH+, 100%);
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7].[CH3:10][O-].[Na+].C=O.[P:15]([O:20]C)([O:18][CH3:19])[O:16][CH3:17]>CO>[CH3:17][O:16][P:15]([CH2:10][NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:7])(=[O:20])[O:18][CH3:19]
Reactant: COP(OC)OC
Reactant: NS(=O)(=O)c1cccs1
Reactant: C[O-]
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COP(=O)(CNS(=O)(=O)c1cccs1)OC
Temperature: 55 °C
Yield: 34 %

Procedure:
To a solution of 2-thiophenesulfonamide (vi) (1.0 g, 6.1 mmol) in methanol (5 mL) was added a catalytic amount of sodium methoxide and paraformaldehyde (200 mg, 6.7 mmol). The reaction was heated to 55° C. for 1 h, and then the homogeneous solution was cooled and trimethyl phosphite (0.8 mL, 6.8 mmol) was added. After heating the reaction mixture for an additional 1 h at 55° C., the reaction mixture was cooled and concentrated. The residue was dissolved in dichloromethane (15 mL), washed with water (10 mL), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (elution with methanol-chloroform; 1:19) yielded (vii) (600 mg, 34%) as a colorless solid: 31P NMR: (162 MHz, CDCl3) δP 23.7. Also isolated was the corresponding N-methylated compound, [(2-thiophenesulfonyl-N-methylamino)methyl]-phosphonic acid dimethyl ester (234 mg, 13%) as a colorless solid: 3C NMR (100 MHz, CDCl3) δC 36.7, 44.6 (d, J=165 Hz), 53.2 (d, J=6.5 Hz), 127.6, 132.4, 132.6, 135.7.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[NH:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:25]=[C:24]2[C:19]([C:20](=[O:31])[C:21]([C:28]([OH:30])=[O:29])=[CH:22][N:23]2[CH2:26][CH3:27])=[CH:18][C:17]=1[F:32]>N1C=CC=CC=1>[CH2:26]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([F:32])=[C:16]([N:11]3[CH2:12][CH2:13][NH:14][CH:9]([CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:10]3)[CH:25]=2)[C:20](=[O:31])[C:21]([C:28]([OH:30])=[O:29])=[CH:22]1)[CH3:27]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: c1ccc(OCC2CNCCN2)cc1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COc4ccccc4)C3)cc21
Temperature: 130 °C
Yield: 46.9 %

Procedure:
A mixture of 2 g of 3-phenoxymethylpiperazine and 701 mg of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of pyridine was heated under argon in a pressure bottle at 130° C. for 18 hours. The solvents were removed and the residue chromatographed on silica gel, eluting with chloroform:methanol (9:1). The appropriate fractions were combined, evaporated, triturated with methanol and ether, then dried, giving 519 mg of the desired compound, mp 198°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:13][C:14]([F:26])([F:25])[C:15]1[N:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:21]([C:18]3[CH:19]=[N:20][C:15]([C:14]([F:26])([F:13])[F:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Reactant: Nc1cc(F)cc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(F)cc2cccnc12)c1ccc(C(F)(F)F)nc1
Yield: 26.3 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-ylamine (Intermediate 48) (150 mg, 0.92 mmol), 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (250 mg, 1.01 mmol) in DCM (2 ml), DMAP (cat), pyridine (146 mg, 1.84 mmol) and DCM (5 ml) gave the title compound (90 mg, 26%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][C:9]([Cl:24])=[CH:10][C:11]=2[Cl:23])[N:6]=1)=[O:4].[OH-].[Na+].Cl>C(O)C.O>[CH2:16]([O:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([Cl:24])=[CH:10][C:11]=2[Cl:23])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a suspension of methyl-4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (1.2 g) in ethanol (20 ml) was added a solution of sodium hydroxide (0.53 g) in water (20 ml) and the mixture was stirred at room temperature for 1 h. Hydrochloric acid (11M) was added until pH2 and the resulting precipitate was filtered off, washed with water (20 ml), ethanol (10 ml), diethylether (5 ml) and dried to yield 4-benzyloxy-5,7-dichloroquinoline-2-carboxylic acid (0.95 g). δ (360 MHz, DMSO-d6), 5.49 (2H, s, CH2), 7.40 (3H, m, m,p-ArH), 7.58 (2H, d, o-ArH), 7.71 (1H, s, 3-H), 7.83 (1H, d, 6-H) and 8.81 (1H, d, 8-H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[CH3:23][N:24]1[C:28]([CH2:29][NH2:30])=[CH:27][N:26]=[CH:25]1>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([NH:30][CH2:29][C:28]3[N:24]([CH3:23])[CH:25]=[N:26][CH:27]=3)=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: COc1ccccc1CN
Reactant: Cn1cncc1CN
Product: COc1ccccc1CNc1ccc2c(NCc3cncn3C)cccc2n1

Procedure:
The title compound, MS: m/e=374.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-bromo-2-chloroquinoline, 2-methoxybenzylamine and (1-methyl-1H-imidazol-5-yl)methylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23](F)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:35]3[CH2:40][CH2:39][S:38][CH2:37][CH2:36]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CSCCN1
Reactant: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Nc2ccc(S(=O)(=O)F)cc2)cc1OC
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Nc2ccc(S(=O)(=O)N3CCSCC3)cc2)cc1OC
Temperature: 90 °C

Procedure:
500 mg (0.95 mmol) of 4-((2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoyl)-amino)-benzenesulfonyl fluoride were dissolved in 1 ml of thiomorpholine and heated to 90° C. for 30 min. For working up the mixture was poured onto 50 ml of ice/1 N hydrochloric acid, the precipitate was filtered off with suction, dried in a vacuum-drying chamber over phosphorus pentoxide and recrystallized from hexane/ethyl acetate. 378 mg (65%) of the title compound having a melting point of 241° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[CH:5]=[C:6]([CH:9]([F:12])[CH2:10][CH3:11])[C:7]=1[Cl:8].CO.C(#N)C.O>Cl.[Cl-].[Cl-].[Cl-].[Ti+3]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH:9]([F:12])[CH2:10][CH3:11])[C:7]=1[Cl:8])[NH2:13]
Reactant: CCC(F)c1cc([N+](=O)[O-])cc(Br)c1Cl
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CCC(F)c1cc(N)cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
6.54 g (22.1 mmol) of 3-bromo-4-chloro-5-(1-fluoropropyl)-1-nitrobenzene was dissolved in a solvent mixture comprising 30 ml of methanol and 90 ml of acetonitrile, followed by the addition of 120 ml of a 20% solution of titanium trichloride in diluted hydrochloric acid under a nitrogen stream under cooling with ice. The obtained mixture was stirred at room temperature for 3 hours and then poured into water. The resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated brine successively, dried and distilled to remove the solvent. The residue was purified by silica gel column chromatography to give 5.04 g of the title compound (yield: 86%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@:9]2([OH:24])[C:13]3=[C:14]([F:23])[CH:15]=[N:16][C:17]4[CH:18]=[C:19]([F:22])[C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][CH2:3]1.[S:25]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].C(Cl)(Cl)[Cl:56].CO>>[ClH:56].[ClH:56].[F:23][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[C:19]([F:22])[C:20](=[O:21])[N:11]3[CH2:10][C@@:9]([OH:24])([CH2:8][N:5]4[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:31]5[N:30]=[CH:29][C:28]6[O:27][CH2:26][S:25][C:33]=6[CH:32]=5)[CH2:7][CH2:6]4)[C:13]=1[C:12]=23
Reactant: ClC(Cl)Cl
Reactant: NC1CCN(C[C@]2(O)Cn3c(=O)c(F)cc4ncc(F)c2c43)CC1
Reactant: O=Cc1cc2c(cn1)OCS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1c(F)cc2ncc(F)c3c2n1C[C@@]3(O)CN1CCC(NCc2cc3c(cn2)OCS3)CC1
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution of (4S)-4-[(4-amino-1-piperidinyl)methyl]-3,8-difluoro-4-hydroxy-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (E1 enantiomer) (180 mg, 0.536 mmol) and [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (89 mg, 0.536 mmol) (for a synthesis, see WO2004058144, Example 61) in chloroform/methanol (5 ml/0.5 ml) was stirred at room temperature under argon for 1 h before treatment with sodium triacetoxyborohydride (341 mg, 1.608 mmol). After 1 h stirring the reaction mixture was treated with saturated sodium bicarbonate (20 ml). The aqueous layer was extracted with a 10% solution of methanol in dichloromethane (3×200 ml). The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was chromatographed eluting with a 0-20% gradient of methanol in dichloromethane to yield 82 mg initially and 13 mg by re-chromatographing mixed fractions of the free base of the title compound as a yellow solid (95 mg, 36%).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[C:15]1([S:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[CH:30]=O)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:32][O:33][C:34](=[O:47])[CH2:35][N:36]1[C:44]2[C:39](=[CH:40][C:41]([F:45])=[CH:42][CH:43]=2)[CH:38]=[C:37]1[CH3:46]>ClCCl.ClCCCl>[CH3:32][O:33][C:34](=[O:47])[CH2:35][N:36]1[C:44]2[C:39](=[CH:40][C:41]([F:45])=[CH:42][CH:43]=2)[C:38]([CH2:30][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:24]=2[S:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:22])=[O:23])=[C:37]1[CH3:46]
Reactant: O=Cc1cnccc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cn1c(C)c(Cc2cnccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 14.1 %

Procedure:
A mixture of triethylsilane (5.1 g), trifluoroacetic acid (3.1 g) and 1,2-dichloroethane (20 mL) at −10° C. was treated dropwise with a mixture of 4-phenylsulfonylpyridine-3-carbaldehyde (1.9 g), (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.66 g) and 1,2-dichloroethane (20 mL), and the resulting mixture was stirred at room temperature for 20 hours. The mixture was treated with additional triethylsilane (5.1 g) and trifluoroacetic acid (3.1 g), and stirred at room temperature for 3 hours and then at 50° C. for 20 hours. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume), followed by trituration with diethyl ether to afford the title compound as a yellow powder (0.19 g).
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:33])[C:5](=O)[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1.[NH3:34]>C(O)C>[NH2:34][C:5]1[C:4](=[O:33])[C:3](=[O:2])[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[NH:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:9]=1
Reactant: N
Reactant: COc1ccc(C(NCCc2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Solvent: CCO
Product: COc1ccc(C(NCCc2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1d), 3-methoxy-4-{3-[(4-methoxyphenyl)-(2-phenylethylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione (1.88 g) [prepared as described in step (c) above] and a solution of ammonia in ethanol (2N, 8.4 ml) were reacted, to give the title compound (1.66 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:4]2[C:9]([C:10]=1[C:11](O)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN(C)C.[NH2:47][CH2:48][C:49]1[C:50](=[O:58])[NH:51][C:52]([CH3:57])=[CH:53][C:54]=1[O:55][CH3:56]>ClCCl.O>[CH3:56][O:55][C:54]1[CH:53]=[C:52]([CH3:57])[NH:51][C:50](=[O:58])[C:49]=1[CH2:48][NH:47][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:2]=1[CH3:1])=[O:12]
Reactant: Cc1c(C(=O)O)c2ccccc2n1C(C)c1ccccc1
Reactant: COc1cc(C)[nH]c(=O)c1CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of 2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxylic acid (66 mg, 0.24 mmol) in anhydrous dichloromethane (5 mL) was added N-hydroxybenzotriazole (38 mg, 0.29 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (55 mg, 0.29 mmol) and trimethylamine (36 mg, 0.36 mmol), and stirred at room temperature for 0.5 hour, 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(1H)-one (40 mg, 0.24 mmol) was added and stirred at room temperature for 16 hours. To the reaction mixture was added water (10 mL), extracted with dichloromethane (10 mL) 2 times, combined and concentrated the organic layers, the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxamide as an off-white solid (0.08 g, 52%). LRMS (M+H+) m/z: calcd 429.21. found 429.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:28]([CH2:32][C:33](Cl)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(#N)C>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:32][C:33]([NH:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]2[C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)=[O:34]
Reactant: Cc1cccc2nc(N)c(-c3cccc(C(F)(F)F)c3)n12
Reactant: CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cccc2nc(NC(=O)CC(C)(C)C)c(-c3cccc(C(F)(F)F)c3)n12
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-ylamine (compound s, 0.05 g, 0.0002 mol) was dissolved in acetonitrile (0.9 mL) and pyridine (0.03 mL, 0.0003 mol). t-butylacetyl chloride (0.028 mL, 0.00020 mol) was added and the mixture was stirred at room temperature for 4 hours. Solvent was removed then ethyl acetate and saturated sodium bicarbonate was added. The layers were separated and the organic layer dried (magnesium sulfate) then removed. The crude product was chromatographed using 60% ethyl acetate/hexanes to give 39 mg of 3,3-Dimethyl-N-(5-methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-yl)-butyramide as a white solid. Rf 0.27, 100% ethyl acetate; MS m/z 390 (M+H). SH-SY5Y_EC50: 0.3399.