Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=CC(O)=C[CH:5]=1.N[C@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Tyr 0.90 (1); Lys 0.21 (1); Arg 0.94 (1)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16](F)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CS(C)=O>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[C:20]([NH:1][CH2:2][C@H:3]([OH:5])[CH3:4])[CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C[C@@H](O)CN
Reactant: N#Cc1ccc(OCc2ccccc2)cc1F
Solvent: CS(C)=O
Product: C[C@@H](O)CNc1cc(OCc2ccccc2)ccc1C#N
Temperature: 125 °C
Reaction time: 48 h

Procedure:
A solution of (R)-(−)-1-amino-propan-2-ol (389 g, 5.19 mol) in dimethyl sulfoxide (600 mL) was added to a solution of the product from Step A (786 g, 3.46 mol), basic alumina (786 g), and 4A molecular sieves (131 g). The stirred mixture was heated at 110-140° C. for 24 h, cooled and filtered, the filter-aide was washed with 10 L of 4:1 ether-ethyl acetate followed by 4 L of 3:2 ethyl acetate-hexane. The organic washes were extracted with water (5 L) and the aqueous phase was extracted with 25% ethyl acetate-hexane (4×2 L). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated to about 3 L and allowed to stand for 48 h. The precipitated solid was collected by filtration, washed with hexane, and vacuum-dried to provide the desired product in two crops (619 g and 86 g). The concentated supernatant was applied to a 5 kg silica gel pad and eluted with a gradient of 10-50% ethyl acetate-hexane to give, after concentration in vacuo, additional product (119 g): total yield was 791 g (81%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[O:12]1[CH2:31][CH:13]1[CH2:14][O:15][C:16](=[O:30])[C:17]1[C:18](=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:19]([O:21][CH2:22][CH:23]1[O:25][CH2:24]1)=[O:20]>>[OH:12][CH:13]([CH2:31][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([OH:1])[CH2:3][C:4]1([CH3:11])[CH3:10])[CH2:14][O:15][C:16](=[O:30])[C:17]1[C:18](=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:19]([O:21][CH2:22][CH:23]([OH:25])[CH2:24][N:5]1[C:4]([CH3:11])([CH3:10])[CH2:3][CH:2]([OH:1])[CH2:7][C:6]1([CH3:9])[CH3:8])=[O:20]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: O=C(OCC1CO1)c1ccccc1C(=O)OCC1CO1
Product: CC1(C)CC(O)CC(C)(C)N1CC(O)COC(=O)c1ccccc1C(=O)OCC(O)CN1C(C)(C)CC(O)CC1(C)C

Procedure:
A mixture of 20.0 g of 4-hydroxy-2,2,6,6-tetramethylpiperidine and 13.9 g of bis(2,3-epoxypropyl)phthalate was reacted following the procedure described in Example 5, to give the desired Compound No. 87 in the form of a white powder. The Compound had an Rf value of 0.24 on thin-layer chromatography on silica gel developed with a 20:4:2:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:29])=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(F)=C(C(NC(C2CCC2)=O)C2C(Cl)=NC=C[N:46]=2)C=CC=1)C1C=CC=CC=1>O=P(Cl)(Cl)Cl>[NH2:46][C:20]1[C:19]2[N:18]([C:17]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[N:16][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[F:29])[CH:23]=[CH:22][N:21]=1
Reactant: Fc1c(OCc2ccccc2)cccc1-c1nc(C2CCC2)n2ccnc(Cl)c12
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1F)c1nccnc1Cl)C1CCC1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3F)c12
Temperature: 55 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
1-(3-Benzyloxy-2-fluorophenyl)-8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine: Cyclobutanecarboxylic acid [(3-benzyloxy-2-fluoro-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]-amide (0.850 g, 2 mmole) was dissolved in POCl3 (6 mL) and heated at 55° C. overnight. The excess POCl3 was removed in vacuo. The residue was cooled to 0° C. and charged with a saturated solution of NH3 in 2-propanol (6 mL). The mixture was left overnight at room temperature. The separated solid was then filtered and washed with methylene chloride. The filtrate was evaporated to dryness and purified by silica-gel column chromatography using hexane:ethyl acetate (60:40) as the eluant to afford the title compound (615 mg, 75%). FAB-MS: m/z 408.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[Cu][C:13]#[N:14]>CN1CCCC1=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[CH2:9][C:10]#[N:11]
Reactant: N#C[Cu]
Reactant: N#CCc1cc(Br)ccc1N
Solvent: O
Solvent: CN1CCCC1=O
Product: N#CCc1cc(C#N)ccc1N
Temperature: 25 °C

Procedure:
2 mmol of (2-Amino-5-bromo-phenyl)-acetonitrile [882855-95-0] and 4 mmol of copper (I) cyanide are heated at 200° C. in 2 ml of N-methylpyrrolidinone for 4 h. After cooling to room temperature, the solution is diluted with water and extracted with ethyl acetate (3×). The organic layer is separated, dried over magnesium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:12]([O-:15])(=[S:14])[CH3:13].[K+]>C(O)C>[C:12]([S:14][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])(=[O:15])[CH3:13]
Reactant: CC([O-])=S
Reactant: O=C(O)c1cccc(CBr)c1
Agent: [K+]
Solvent: CCO
Product: CC(=O)SCc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 3-(bromomethyl)benzoic acid (7 g, 32.56 mmol, 1.00 equiv) in ethanol (80 mL), and potassium thioacetate (9.65 g, 84.65 mmol, 2.60 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 80 mL of water and adjusted to pH 3-4 with 10% hydrochloric acid. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×50 mL of brine, dried over sodium sulfate, and concentrated under vacuum. This resulted in 4.4 g (64%) of 3-(acetylthiomethyl)benzoic acid as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[OH:14][C:12]([CH3:15])([CH3:13])[CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(O)CCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)COc1ccc(C=O)cc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
5 g (40.94 mmol) of 4-hydroxybenzaldehyde were initially charged in 50 ml of DMF. 4.45 g (40.94 mmol) of 1-chloro-2-methylpropan-2-ol and 6.08 g (57.32 mmol) of sodium carbonate were added, and the mixture was then stirred at 130° C. overnight. Saturated aqueous sodium bicarbonate solution/ethyl acetate were added to the reaction mixture. The precipitate was filtered off and discarded. The two phases were separated from one another, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated using a rotary evaporator. The residue was purified by column chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 5/1→1/2).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2([C:24]([F:27])([F:26])[F:25])[O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:7]2=3)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(O[N:50]1[C:55](=[O:56])[CH2:54][CH2:53][C:51]1=[O:52])=[N+](C)C)C>C1COCC1>[O:52]=[C:51]1[CH2:53][CH2:54][C:55](=[O:56])[N:50]1[O:22][C:21](=[O:23])[CH2:20][CH2:19][CH2:18][O:17][C:15]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:6]([C:5]#[C:4][CH:1]3[CH2:3][CH2:2]3)([C:24]([F:27])([F:26])[F:25])[C:7]=2[CH:16]=1
Reactant: O=C(O)CCCOc1ccc2c(c1)C(C#CC1CC1)(C(F)(F)F)OC(=O)N2
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCOc1ccc2c(c1)C(C#CC1CC1)(C(F)(F)F)OC(=O)N2)ON1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
A solution of 35 mg (0.091 mmol) of the acid 11 in 2 mL of anhydrous THF was cooled to 0° C., and 30 μL (0.15 mmol) of N,N-diisopropylethylamine was added followed by 40 mg (1.28 mmol) of O-(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate. The reaction mixture was allowed to warm up to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP preparative HPLC using acetonitrile and water as a mobile phase containing 0.1% of trifluoroacetic acid to give 30 mg (00.62 mmol, 68%) of 12 as a white powder [LC-MS; M+H 481.0].
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.O1CCCC1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2c([N+](=O)[O-])cccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nccc2c(N)cccc12
Yield: 88 %

Procedure:
1-Methyl-5-nitroisoquinoline (prepared according to Rathelot, P. et al. Eur. J. Med. Chem. 1995, 30, 503-508.) (2.19 g, 11.64 mmol) was dissolved in methanol (20 mL) and tetrahydrofuran (20 mL) in a 250 mL stainless steel pressure bottle to which was added 5% Pd—C (0.438 g, 4.12 mmol). The reaction mixture was stirred for 2 h under 30 psi hydrogen at ambient temperature. The mixture was filtered through a nylon membrane and the volatiles evaporated in vacuo. The resulting grayish solid was triturated with 1:1 hexanes-CH2Cl2 (50 mL) and the title compound (1.62 g, 10.24 mmol, 88%) was collected as an off white solid. MS (DCI/NH3) m/z 159 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[CH:18]=[C:17]([C:19]3([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)[CH:16]=[CH:15][C:13]=2[N:14]=1)[CH:5]=O.Cl.[NH:29]1[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][N:29]2[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[CH:18]=[C:17]([C:19]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][CH2:21]3)[CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)cc3s2)c(F)c1
Reactant: COC(=O)C1CNC1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)cc4s3)c(F)c2)C1

Procedure:
Reaction of 3-fluoro-4-(6-(1-phenylcyclopropyl)benzo[d]thiazol-2-yl)benzaldehyde (0.050 g, 0.13 mmol) and methyl azetidine-3-carboxylate hydrochloride (0.030 g, 0.20 mmol) according to Reference R and general procedure for reductive amination afforded methyl 1-((3-fluoro-4-(6-(1-phenylcyclopropyl)benzo[d]thiazol-2-yl)phenyl)methyl)azetidine-3-carboxylate. MS (ESI) m/z: Calculated: 472.2; Observed: 473.1 (M++1).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:14]3)[CH:7]=[CH:8][CH:9]=2)[N:4]=1)=O.[I:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:35][NH2:36])[CH:30]=1>C(Cl)Cl>[I:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:35]/[N:36]=[CH:1]/[C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[C:6]([N:13]4[CH2:14][CH2:15][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:17][CH2:18]4)[CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH:30]=1
Reactant: NNc1cc(I)ccn1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C=O)nc23)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(/C=N/Nc4cc(I)ccn4)nc23)CC1
Reaction time: 1 h

Procedure:
To tert-butyl (1-(2-formylquinolin-8-yl)piperidin-4-yl)methylcarbamate (112 mg, 0.303 mmol) in DCM (20 mL) was added 1-(4-iodopyridin-2-yl)hydrazine (78.4 mg, 0.333 mmol). The reaction mixture was stirred for 1 hour and then taken on to directly to the next step.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[CH2:12]Br)(=O)C.[CH:15]([NH2:17])=[S:16].C(N)=O>CC(C)=O>[S:16]1[CH:12]=[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[OH:4])[N:17]=[CH:15]1
Reactant: CC(=O)Oc1ccccc1C(=O)CBr
Reactant: NC=S
Solvent: CC(C)=O
Solvent: NC=O
Product: Oc1ccccc1-c1cscn1
Temperature: 10 °C

Procedure:
o-(Bromoacetyl)phenyl acetate (5.0 g, 19.5 mmol) was treated with crude thioformamide (filtrate concentrated in vacuo from reaction of P2S5 (1.1 eq.) and (25 mmol) formamide in THF (30-40° C., 5 hours)) in refluxing acetone (60 mL). After 16 hours the reaction mixture was cooled to about 10° C. and the precipitated HBr salt of 2-(thiazol-4-yl)phenol was recovered. 31%, 1.50 g, LSIMS m/z=178 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[H][H]>[Ni].C(Cl)Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.76 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml), Raney Nickel (0.15 g wet basis) and DCM (12.5 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.76%].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]2=[O:31])[CH:19]=[CH:20][C:21]=1[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:18]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([CH3:15])[CH:17]=2)[C:24]1=[O:31])=[O:29]
Reactant: Cc1ccc(N2CCC(C(=O)O)C2=O)cc1C
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1C
Yield: 51.8 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(3,4-dimethylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.105 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.090 g (52%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(3,4-dimethylphenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([OH:30])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26])#[CH:19]>C(N(CC)CC)C.O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:30][C:23]1[CH:22]=[CH:21][C:20]([C:18]#[C:19][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: C#Cc1ccc(O)c(C(=O)OC)c1
Reactant: O=S(=O)(Nc1ccccn1)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Temperature: 60 °C

Procedure:
4-Iodo-N-(2-pyridinyl)benzenesulfonamide (35 g, 97 mmol) was dissolved in a mixture of triethylamine and tetrahydrofuran (750+750 ml). The mixture was deaerated with nitrogen and dichlorobis(triphenylphosphine)palladium (1.2 g, 1.7 mmol) and copper(I) iodide (0.6 g, 3.4 mmol) were added. Finally methyl 5-ethynyl-2-hydroxybenzoate (23 g, 130 mmol) was added. The mixture was heated to 60° C. for 4 h, evaporated to dryness. The residue was dissolved in chloroform (1000 ml) and washed with water (3×200 ml) and dried with MgSO4. The solvent was evaporated in vacuo. Yield 31 g (77%). The product can be purified by flash-chromatography on silica with chloroform as the eluent.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:21])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:5][CH2:6][C:7]=1[C:8](=[O:11])[CH2:9][CH3:10].[C:22](=O)([O-])[O-].[Cs+].[Cs+].S(OC)(OC)(=O)=O>CN(C)C=O>[CH3:22][O:1][C:2]1[C:3](=[O:21])[N:4]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:5][CH2:6][C:7]=1[C:8](=[O:11])[CH2:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)C1=C(O)C(=O)N(Cc2ccc(OC)cc2)CC1
Agent: [Cs+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CCC(=O)C1=C(OC)C(=O)N(Cc2ccc(OC)cc2)CC1

Procedure:
3-Hydroxy-1-(4-methoxybenzyl)-4-propionyl-5,6-dihydro-1H-pyridin-2-one (17.35 kg, 60 moles) and cesium carbonate (22.126 kg, 67.9 moles) were added to dry dimethylformamide (24 gal, 90.8 L) in a clean, dry 100 gallon tank. The suspension was stirred a half hour to insure dispersion. Dimethyl sulfate (8.552 kg, 67.8 moles) was added neat over a period of 30 minutes keeping the temperature 20-25° C. When the charge was complete the addition funnel was rinsed into the tank with additional DMF (500 ml). The reaction was allowed to stir at 20-25° C. for 16 hours. The reaction was diluted with ethyl acetate (108 gal, 408.8 L) and was washed with water (4×22 gal (83.3 L)). The ethyl acetate solution was washed with a solution made up of 6.94 liters 50% sodium hydroxide in 22 gal (83.3 L) of water followed by washing with a solution made up with 6.94 liters of concentrated HCl in 22 gal (83.3 L) of water. The organic solution was dried by washing with brine (14 gal, 53 L) The ethyl acetate was vacuum stripped to an oil which was suitable for use in the next step. The estimated yield based on NMR analysis of residual solvent was 89%. A small sample was isolated for characterization.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8](#N)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(O)C>[C:9]1([C:8]2[S:4][CH2:3][CH:2]([C:5]([OH:7])=[O:6])[N:1]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1ccccc1
Reactant: N[C@@H](CS)C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)C1CSC(c2ccccc2)=N1
Yield: 66 %

Procedure:
Cysteine, benzonitrile, and 5 equivalents of triethylamine were refluxed in ethanol for 6-8 hours to obtain a 66-70% yield of 2-phenylthiazoline-4-carboxylic acid. The 2-phenylthiazoline-4 carboxylic acid was reacted with 2.05 equivalents of base and 1 equivalent of methyl iodide in tetrahydrofuran at 0° C. to form 2-phenyl-4-methylthiazoline-4 carboxylic acid. The 2-phenyl-4-methylthiazoline-4 carboxylic acid can be resolved and isolated as the (S)-enantiomer using emulsion crystallization, and subsequently hydrolyzed with hydrochloric acid, thereby obtaining (S)-2-methylcysteine hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[CH:2].N1C2C(=CC=CC=2)C=CC=1>C(OCC)C.[Pd]>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[CH2:2]
Reactant: C#Cc1ccc(O)c(C(=O)OC)c1
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: C=Cc1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 5-ethynyl-2-hydroxybenzoate (8 g, 45.4 mmol), prepared according to Example 1b, was dissolved in a mixture of diethyl ether and light petroleum (200+200 ml) in a hydrogenation flask. Quinoline (1.7 ml) and palladium on CaCO3, poisoned with Pb (Lindlar catalyst; 200 mg) were added, and the flask was attached to an atmospheric pressure hydrogenation apparatus. The mixture was stirred for 2 h at room temperature, by then the calculated amount of hydrogen had been consumed. The catalyst was filtered off and the solution was evaporated to dryness. The product was purified by flash column chromatograpy on silica, using toluene as an eluent. A nearly quantitative yield was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Cl:16])[NH:12][CH:11]=[CH:10]2.[OH-].[Na+].O.CN([CH:23]=[O:24])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Cl:16])[NH:12][CH:11]=[C:10]2[CH:23]=[O:24]
Reactant: Clc1cc2[nH]ccc2cc1Br
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A round-bottom flask was charged with DMF (54 mL). Phosphorus oxychloride (6.21 mL, 66.8 mmol) was added dropwise over 5 minutes, and the reaction mixture was stirred at room temperature for an additional 5 minutes. A solution of 5-bromo-6-chloro-1H-indole (7700 mg, 33.41 mmol) in DMF (7 mL) was added dropwise to the reaction mixture, which caused a precipitate to form. The reaction mixture was then heated to 95° C. for 25 minutes. The reaction mixture was treated with 1N aqueous sodium hydroxide (170 mL) and water (170 mL). The reaction mixture was stirred at 95° C. for 11 minutes. The reaction mixture was cooled to 0° C., and the solids were collected by filtration. The solids were washed with water (50 mL) and diethyl ether (50 mL) and dried in vacuo for 16 hours at 65° C. to afford the title compound (7.77 g, 90%) as a tan solid. MS (AP+) 257.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.40 (s, 1H), 8.38 (s, 1H), 7.80 (s, 1H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+](C)([O-])=O.[CH3:9][N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:20].ClC[CH:23]([O:26]C(CCl)CCl)CCl>C(Cl)Cl>[CH3:9][N:10]1[C:15]2[CH:16]=[C:17]([CH:23]=[O:26])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:20]
Reactant: CN1C(=O)COc2ccccc21
Reactant: ClCC(CCl)OC(CCl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: CN1C(=O)COc2ccc(C=O)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
1 g of AlCl3 were suspended in 10 ml DCM, 0.5 ml of nitromethane were added to dissolve AlCl3, and the solution was cooled to 0° C. 4-Methyl-4H-benzo[1,4]oxazin-3-one (0.5 g, 3.06 mmol) dissolved in DCM was added to the above solution and stirred for 15 minutes at 0° C. To this solution was further added 0.36 ml of bis-chloromethyl-methylether in DCM. The reaction was stirred at 0° C. for 15 minutes and at room temperature for 3 h. The crude reaction mixture was then poured onto ice, the layers were separated and the organic phase was washed with NaHCO3 and brine. After drying over MgSO4 and filtration the solvent was evaporated, which afforded 0.43 g of crude product. The dark oil was purified by flash chromatography using EtOAc and cyclohexane as eluents, affording 0.2 g (37%) of 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde as colourless solid.