Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[C:19]([O:23][C:24](=[O:44])[N:25]([CH3:43])[C@@H:26]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1)[CH3:27])([CH3:22])([CH3:21])[CH3:20]>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:31]1[CH:30]=[CH:29][C:28]([C@H:26]([N:25]([CH3:43])[C:24](=[O:44])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])[CH3:27])=[CH:33][CH:32]=1
Reactant: C[C@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N(C)C(=O)OC(C)(C)C
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)N(C)C(=O)OC(C)(C)C)cc1
Yield: 66 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.46 mmol) was reacted with (R)-tert-butylmethyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (250 mg, 0.69 mmol to afford the desired product (145 mg, 66%) as a light brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]1([NH:15][NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[C:9]1([NH:15][N:16]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNc1ccccc1
Reactant: O=Cc1cccnc1
Solvent: CCO
Product: C(=NNc1ccccc1)c1cccnc1

Procedure:
10.8 g of 3-pyridinecarbaldehyde was dissolved in 30 ml of ethanol. 10.8 g of phenylhydrazine was added to the stirred solution, at room temperature. 3 crystallized out as yellow prisms, mp 158-160.5° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([NH2:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>O1CCCC1>[NH2:13][C:11](=[S:24])[C:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:14])[CH3:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Yield: 48.8 %

Procedure:
N2-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalaninamide (3.87 g, 19.13 mmol), Lawesson's reagent (7.74 g, 19.13 mmol) and tetrahydrofuran (THF) (100 mL) was heated to 50° C. for 3 hours. The reaction was concentrated, added 150 cc of EtOAc and washed with sat'd NaHCO3 (3×100 cc), water and brine. The EtOAc layer was concentrated and the residue was purified via chromatography on silica gel eluted Hex to 1:1 Hex/EtOAc to obtain the title compound (2.04 g, 48% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([O:28][CH3:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>C(#N)C.O>[CH:30]([NH:33][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([O:28][CH3:29])[CH:11]=2)=[O:22])=[C:16]([CH3:27])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:32])[CH3:31]
Reactant: COc1cc(-c2nc3c(C)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Reactant: CC(C)N
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)Nc2c(C)cc3cn[nH]c3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 500 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of 4:1 (v/v) mixture of acetonitrile/water is added 1.0 mL (12.2 mmol) of isopropylamine. The reaction mixture is stirred during 1 hour at ambient temperature and for 2.5 hours at 60° C. and then concentrated in vacuo. The residue is taken-up with brine and tert-butylmethylether. The phases are separated and the aqueous layer is washed with tert-butylmethylether. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 3:7) affords 118 mg (19% over two steps) of the product as white solid; LC/MS:468/470 (M+H)+, m.p.: 148-151° C.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].Cl>>[Cl:16][C:10]1[CH:9]=[CH:8][C:7]2[N:6]=[C:3]([CH3:4])[CH:2]=[CH:1][C:15]=2[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: C/C=C/C=O
Agent: Cl
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: Cc1ccc2c(C(=O)O)c(Cl)ccc2n1

Procedure:
Crotonaldehyde (1.5 mL) was added dropwise over a period of 1 hour to a mixture of 5-amino-2-chlorobenzoic acid (1.7 g), ferrous sulphate heptahydrate (0.77 g), sodium m-nitrobenzenesulphonate (1.2 g) and concentrated hydrochloric acid (11 mL) at 95° C. The reaction mixture was heated for a further 15 minutes then filtered whilst still hot. The collected solid was extracted with boiling 2M aqueous hydrochloric acid solution (20 mL) and the extract combined with the filtrate. Ammonium acetate was then added to give a solution of pH 4, which was cooled in ice and the resultant precipitate collected by filtration and washed with water. The product was converted to its hydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane) and the solid dried in vacuo to give the sub-title compound (0.5 g) as a solid.
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[Cl:11][C:12]1[CH:18]=[C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH2:14].[C:34]1([CH2:40][C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C(O)C>[C:34]1([CH2:40][C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl:11][C:12]1[CH:18]=[C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH:14][C:44]([NH:43][C:41](=[O:42])[CH2:40][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[S:45]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C(Cc1ccccc1)N=C=S
Agent: O=C(Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
2-Phenylethanoyl isothiocyanate was prepared using commercially available 2-phenylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-phenylethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (48 mg, yield 62%).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([CH2:27][NH:28][CH:29]([CH3:31])[CH3:30])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH:16]1([CH2:15][CH2:14][CH2:13][C@@H:12]([C:22]2[O:23][CH:24]=[C:25]([CH2:27][NH:28][CH:29]([CH3:31])[CH3:30])[N:26]=2)[CH2:11][C:10]([NH:9][OH:8])=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)NCc1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)NCc1coc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 43 °C

Procedure:
A solution of (3R)-N-(benzyloxy)-6-cyclohexyl-3-{4-[(isopropylamino)methyl]-1,3-oxazol-2-yl}hexanamide (preparation 157) (85 mg, 0.20 mmol) in EtOH (5 ml) was treated with HCO2NH4 (63 mg, 1.00 mmol) and Pd(OH)2 (20 mg) and the reaction mixture heated at 43° C. for 18 hours. 2 further portions of HCO2NH4 (30 mg+30 mg) and Pd(OH)2 (10 mg+30 mg) were added over a period of 4 hours. The catalyst was filtered off and washed with EtOH. The solvent was removed under reduced pressure. The crude material was purified on a silica column eluting with DCM:MeOH:NH3 (90:10:1) to afford the title compound.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C-:11]#[N:12].[Na+]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[C:11]([CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:12]
Reactant: CCOC(=O)C[C@H](O)CCl
Reactant: [C-]#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(=O)C[C@H](O)CC#N

Procedure:
To a well stirred solution of ethyl (S)-4-chloro-3-hydroxybutyrate (8.25 g, 50 mmoles) in 300 mM potassium phosphate buffer, 300 mM NaCN pH 8.0 (1L) at 30° C. was added halohydrin dehalogenase SEQ ID NO: 14 (9 g) as a lyophilized powder. After fifty seven hours the mixture was washed with ethyl acetate (2 times 250 mL) and the combined organics dried over anhydrous sodium sulfate. The mixture was filtered and evaporated on a rotary evaporator to give essentially pure ethyl (R)-4-cyano-3-hydroxybutyrate, as determined using the gas chromatography method and elution time data described in Example 6, hereinbelow.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:18])=[O:17])=[CH:8]2)=[C:4]([F:21])[CH:3]=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1.O>[F:21][C:4]1[CH:3]=[C:2]([C:26]2[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=2)[CH:20]=[CH:19][C:5]=1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=[O:17])=[CH:8]1
Reactant: O=C(O)c1cn(Cc2ccc(Br)cc2F)c2ccccc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2ccc(Cn3cc(C(=O)O)c4ccccc43)c(F)c2)cn1
Temperature: 150 °C

Procedure:
In a 5 mL microwave vial, 1-(4-bromo-2-fluorobenzyl)-1H-indole-3-carboxylic acid (70 mg, 0.20 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (90 mg, 0.43 mmol), cesium carbonate (250 mg, 0.77 mmol), and Pd(dppf)Cl2 (20 mg, 0.02 mmol) was massed. The vial was then charged with a stir bar and 3 mL of 5:1 THF/H2O. The vial was capped and heated to 150° C. for 30 min. The reaction was cooled to ambient temperature and deemed to be complete by LCMS. The reaction mixture was diluted with H2O (20 mL) and dichloromethane (20 mL), and the organic layer was acidified to pH 1 with 1M HCl. The aqueous layer was extracted with dichloromethane (3×20 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with hexanes/ethyl acetate (0 to 100%) to afford 1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1H-indole-3-carboxylic acid (LCMS: M+H=350, RT=0.687 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([Cl:19])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([Cl:22])[C:15]3[C:10](=[CH:11][C:12]([Cl:19])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)nc2cc(Cl)ccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ccc2c(Cl)nc(-c3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(4-Bromo-phenyl)-7-chloro-3H-quinazolin-4-one (38.7 mmol) is added to 50 ml thionylchloride and is heated at 40°. The mixture is treated with 6 ml dimethylformamide (DMF). After cooling to rt the mixture is stirred for 3 hrs. Customary working up gives 2-(4-bromo-phenyl)-4,7-dichloroquinazoline as a solid; m.p. 189-190°.
Reaction SMILES: C(N(CC)CC)C.C(O[CH:11]=[C:12]([C:18]#[N:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C.C(O)(=O)C(O)=O.[CH2:26]([NH:28][NH2:29])[CH3:27]>C(O)C>[CH2:16]([O:15][C:13]([C:12]1[CH:11]=[N:29][N:28]([CH2:26][CH3:27])[C:18]=1[NH2:19])=[O:14])[CH3:17]
Reactant: CCNN
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(CC)c1N
Yield: 80.1 %

Procedure:
Triethylamine (19.6 ml, 144 mmol) was added cautiously to a solution of ethyl (ethoxymethylene)cyanoacetate (10.1 g, 60 mmol) and ethyl hydrazine oxalate (9.9 g, 66 mmol) in ethanol (200 ml). The mixture was heated at reflux for 24 h then concentrated in vacuo. The residue was redissolved in EtOAc, washed with 5% KHCO3 solution then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 25% pet. ether:75% EtOAc) to yield the title compound (8.8 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][F:29])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][F:29])=[CH:24][CH:25]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: FCCOc1ccc(CBr)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OCCF)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 1-(bromomethyl)-4-(2-fluoroethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions F): tR=0.80 min.; [M+H]+: 388.23 g/mol.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[F:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[CH:44][C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:43]2[CH:44]=[C:45]([F:49])[CH:46]=[C:47]([F:48])[C:42]=2[F:41])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: OB(O)c1cc(F)cc(F)c1F
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4cc(F)cc(F)c4F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,5-trifluorophenyl)boronic acid gave 263. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.88-7.79 (m, 1H), 7.68-7.54 (m, 4H), 4.96 (dd, J=8.7, 3.5 Hz, 1H), 4.06 (dd, J=13.1, 4.2 Hz, 1H), 3.92 (dd, J=13.2, 6.0 Hz, 1H), 3.77 (s, 3H), 3.70-3.64 (m, 1H), 3.46-3.41 (m, 1H), 3.27 (s, 3H), 2.18-2.10 (m, 1H), 1.94-1.82 (m, 2H), 1.75-1.67 (m, 1H). LCMS (ES+) m/z 497 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:43]1([CH2:47][C@H:48]([CH:51]2[CH2:53][CH2:52]2)[NH:49][CH3:50])[CH2:46][CH2:45][CH2:44]1>C(Cl)Cl>[N:43]1([CH2:47][C@@H:48]([N:49]([CH3:50])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=2)[CH:51]2[CH2:53][CH2:52]2)[CH2:46][CH2:45][CH2:44]1
Reactant: CN[C@H](CN1CCC1)C1CC1
Reactant: Cc1cc(C(=O)O)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N(C)[C@H](CN2CCC2)C2CC2)ccc1F
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
To a mixture of 4-fluoro-3-methylbenzoic acid (330 mg, 2.14 mmol) and DIPEA (0.508 mL, 2.92 mmol) in DCM (3 mL) was TBTU (687 mg, 2.14 mmol) added. After 10 min was a solution of (S)-2-(azetidin-1-yl)-1-cyclopropyl-N-methylethanamine (Compound L1) (300 mg, 1.94 mmol) in DCM (3 mL) added. The resultant mixture was stirred at r.t for 6 h. The mixture was washed with NaHCO3 (8% aq., 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (353 mg, 63%). Mixture of rotamers: 1H NMR (600 MHz, CD3OD) δ 0.04-0.14, 0.31-0.40, 0.40-0.48, 0.48-0.57, 0.59-0.66, 0.67-0.75, 0.92-1.06, 2.01-2.07, 2.07-2.16, 2.29, 2.30, 2.56-2.65, 2.76-2.88, 2.90, 2.94-3.00, 3.02, 3.09-3.21, 3.26-3.37, 3.80-3.91, 7.04-7.14, 7.22-7.40. Total no of protons: 23. HRMS (M+H)+: calculated 291.1873. found 291.1865.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)([CH3:16])[CH3:15]
Reactant: CC(C)Br
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OC(C)C)cc1
Yield: 79.8 %

Procedure:
Methyl 2-(4-hydroxyphenyl)acetate (10 g, 60.2 mmol), 2-bromopropane (6.49 mL, 69.2 mmol), and potassium carbonate (8.32 g, 60.2 mmol) were heated to 50° C. in DMF (100 mL) for overnight. The reaction was filtered and the organic layer was concentrated under vacuum. The crude material was purified by silica gel chromatography using a gradient of 0-20% EtOAc/hexanes. The product fractions were collected and the solvent removed under vacuum to give methyl 2-(4-isopropoxyphenyl)acetate (10 g, 80% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.14 (m, 2H), 6.88-6.82 (m, 2H), 4.53 (spt, J=6.1 Hz, 1H), 3.70 (s, 3H), 3.57 (s, 2H), 1.34 (d, J=6.0 Hz, 6H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22](O)=[O:23]>>[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:23]
Reactant: CC(C)(C)CC(=O)O
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: CC(C)(C)CC(=O)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 3,3-dimethylbutanoic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.2 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.00 (m, 1H), 7.89-7.93 (m, 1H), 3.79-3.84 (m, 4H), 3.08-3.13 (m, 4H), 2.16 (s, 2H), 1.07 (s, 9H); MS (ESI−) M/Z 343 (M−H)−.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:30]=1[CH:31]=[CH:32][C:33](O)=[O:34]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:33](=[O:34])[CH:32]=[CH:31][C:30]1[CH:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:29]=1[O:28][CH3:27])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1
Product: COc1ccc(C=CC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c(OC)c1
Yield: 72 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 2,4-dimethoxycinnamic acid under the conditions described in example 86 to yield 72% of the desired product.
Reaction SMILES: [BH4-].[Na+].O[N:4]=[C:5]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH:9]1[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CO.[Mo](=O)(=O)=O>[NH2:4][CH:5]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH:9]1[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CC1CN(CCSc2cccs2)CCC1CCC(=NO)c1c(F)cnc2ccc(OC)cc12
Agent: O=[Mo](=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1CN(CCSc2cccs2)CCC1CCC(N)c1c(F)cnc2ccc(OC)cc12
Temperature: -5 °C
Yield: 37.2 %

Procedure:
0.695 g of sodium borohydride was added in several portions to a mixture of 0.98 g of methyl (3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate in 50-cm3 of methanol cooled to the region of −5° C., with stirring and under inert atmosphere. The reaction was very exothermic and in the vicinity of 0° C., 0.365 g of molybdenum trioxide were added all at once. The reaction mixture was stirred in the region of 20° C. for 20 hours and then it was cooled to the vicinity of −6° C. and 0.695 g of sodium borohydride and 0.365 g of molybdenum trioxide were again added. The reaction mixture was stirred for 5 hours in the region of 20° C. and was then filtered on celite and the insoluble matter was washed twice with 50-cm3 of methanol. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 m; diameter 3 cm; height 25 cm), eluting with a successive mixture of cyclohexane-ethyl acetate (50/50 by volume), ethyl acetate and then dichloromethane-methanol (90/10 by volume) and collecting 50-cm3 fractions. Fractions 17 to 20 were combined and then concentrated to dryness according to the conditions described above. 0.355 g of methyl (3RS,4RS)-4-[3-(R,S)amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate were obtained in the form of a colorless oil.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH:6]([CH3:17])[CH2:7][NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16].O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:2][CH:6]([CH3:17])[CH2:7][NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16]
Reactant: Cc1cccc(C)c1NCC(C)O
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1NCC(C)Br
Reaction time: 6 h
Yield: 87.5 %

Procedure:
A mixture of 250 ml (712 g, 2.63 moles) of phosphorous tribromide and 250 ml of dry chloroform is added dropwise to a solution of 100 g (0.558 moles) of N-(β-hydroxypropyl)-2,6-dimethyl-aniline in 500 ml of dry chloroform. During the addition the temperature of the mixture is maintained below +25° C. by cooling with icy water. The resulting mixture is boiled for 6 hours, thereafter it is cooled on salted ice, and 100 ml of water are added dropwise. The pH of the resulting mixture is adjusted to 9 with 10 n aqueous sodium hydroxide solutions. The phases are separated from each other, and the aqueous phase is extracted thrice with 300 ml of chloroform each. The organic solutions are combined, washed four times with 500 ml of water each, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. 118.2 g (87.5%) of N-(β-bromopropyl)-2,6-dimethyl-aniline are obtained as a colourless oily residue. This product is sufficiently pure to be applied directly in the next step. When distilling the oil at 0.3 mm Hg it boils at 102°-106° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([F:18])[CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccnc(F)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (67 mg, 81%), MS (ISP) m/z=330.5 [(M+H)+], mp 290.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8 mg, 0.325 mmol).