Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25]([OH:27])=O)[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.CN(C=O)C.[CH2:41]([NH:48][CH2:49][CH2:50][O:51][CH3:52])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1(C)C=CC=CC=1.ClCCl.C(N(CC)CC)C>[CH2:41]([N:48]([CH2:49][CH2:50][O:51][CH3:52])[C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:16](=[O:31])[N:17]2[C:22]=1[C:21]1[S:28][CH:29]=[CH:30][C:20]=1[CH:19]=[CH:18]2)=[O:27])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COCCNCc1ccccc1
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COCCN(Cc1ccccc1)C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12

Procedure:
From 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with SOCl2 and DMF in toluene. Then treatment with triethylamine and benzyl-(2-methoxy-ethyl)-amine in dichloromethane. MS-ISP: 575 (M+H)+.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@H:17]([C@@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(O)C.O>>[NH2:23][C@:22]([C@@H:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH2:18]1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@@H]([C@@]2(C)COC(=O)N2)C3)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@@H]([C@](C)(N)CO)C3)CC1

Procedure:
The mixture of (S)-4-((R)-6-(trans-4-tert-butylcyclohexyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one (109.3 mg, 0.0002835 mol) (isomer 1) and lithium hydroxide (74.7 mg, 0.00312 mol) in ethanol (1.8 mL, 0.031 mol) and water (0.60 mL, 0.033 mol) was heated to reflux for overnight. LCMS showed starting material was consumed and peak Rf=1.66 min 360.39 ([M+1], 100%) left. The solvent was removed under vacuum and the residue was partitioned between water and dichloromethane. The aqueous layer was extensively extracted with dichloromethane. And the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into dichloromethane and subjected to chromatography purification with dichloromethane/MeOH (10:90 to 80:20) to give the product (17.3 mg, 17% yield). LCMS 360.39 ([M+1], 100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.89 (s, 9H), 1.07 (s, 3H), 1.09-1.54 (m, 6H), 1.79-1.87 (m, 3H), 2.04 (m, 1H), 2.15 (m, 2H), 2.53 (dd, J=15.5, 12.3 Hz, 1H), 2.72-2.86 (m, 3H), 3.46 (d, J=11.0 Hz, 1H), 3.55 (d, J=11.0 Hz, 1H), 4.07 (m, 1H), 6.59 (d, J=2.4 Hz, 1H), 6.63 (dd, J=8.3, 2.5 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C=O)C.CCOC(C)=O>[CH3:16][N:17]([CH3:19])[CH:18]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Cc1ccc(F)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN(C)C)c1ccc(F)cc1
Yield: 34.3 %

Procedure:
Combined ethyl 2-(4-fluorophenyl)acetate (500 mg, 2.74 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (1.837 mL, 13.72 mmol) and DMF (2 mL) and heated at 100° C. for 5 h. The reaction was then diluted with EtOAc (50 mL), washed with saturated aqueous ammonium chloride (50 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified on a 30 g NH silica column (Moritex) eluted with 0 to 60% EtOAc in hexanes to give the title compound (223 mg, 34.2% yield) as a clear, colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.1 Hz, 3 H) 2.64 (s, 6 H) 3.98 (q, J=7.1 Hz, 2 H) 7.06-7.15 (m, 4 H) 7.49 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[NH2:29].Cl>O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:29][C@@H:24]2[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]2[CH3:22])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: C[C@@H]1CCCC[C@H]1N
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N[C@@H]2CCCC[C@H]2C)c([N+](=O)[O-])c1
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
To a solution of 6.47 g of 4-fluoro-3-nitro-benzoic acid methyl ester in 35 ml of abs. DMF was added 13.47 g of potassium carbonate, followed by 4.96 g of (1R,2R)-2-Methyl-cyclohexylamine-hydrochloride. After 1.5 h at 60° C., the mixture was poured into water, the pH was adjusted to 5-6 by the addition of 2 M aqueous hydrochloric acid, and the reaction mixture was extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over sodium sulphate and concentrated to yield 9.28 g (98%) of 4-((1R,2R)-2-Methyl-cyclohexylamino)-3-nitro-benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:17][N:18]([CH3:36])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)=[O:27])=[CH:21][CH:20]=1>>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:15]=[CH:14][C:12]4[N:13]=[C:32]([C:31]5[CH:34]=[CH:35][C:28]([C:26]([NH:25][C:22]6[CH:23]=[CH:24][C:19]([N:18]([CH3:36])[CH3:17])=[CH:20][CH:21]=6)=[O:27])=[CH:29][CH:30]=5)[NH:16][C:11]=4[CH:10]=3)=[CH:3][C:2]=2[N:1]=[C:32]1[C:31]1[CH:30]=[CH:29][C:28]([C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([N:18]([CH3:17])[CH3:36])=[CH:20][CH:21]=2)=[O:27])=[CH:35][CH:34]=1
Reactant: CN(C)c1ccc(NC(=O)c2ccc(C=O)cc2)cc1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Product: CN(C)c1ccc(NC(=O)c2ccc(-c3nc4cc(-c5ccc6nc(-c7ccc(C(=O)Nc8ccc(N(C)C)cc8)cc7)[nH]c6c5)ccc4[nH]3)cc2)cc1

Procedure:
Compound 267 was prepared according to the procedure similar to that described in Scheme III from 3,3′-diaminobenzidine and 4-(4-dimethylaminophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C44H38N8O2: 711.31; found: 711.38.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:16]([CH:13]1[CH2:15][CH2:14]1)[CH2:11]2
Reactant: NC1CC1
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Solvent: CO
Product: O=C1c2ccc(Br)cc2CN1C1CC1
Yield: 85.7 %

Procedure:
Methyl 4-bromo-2-(bromomethyl)benzoate (1A2) (1.62 mmol, 500 mg) and cyclopropylamine (1A3) (3.25 mmol, 185 mg) in methanol (3 ml) were heated in the microwave at 120° C. for 10 mins. The reaction mixture was concentrated and purified on silica eluting with 50-100% EtOAc/heptane to yield 5-bromo-2-cyclopropylisoindolin-1-one (1A4) 350 mg (84%); 1H NMR (400 MHz, CDCl3) δ 7.96 (d, 1H) 7.59 (d, 1H) 7.78 (s, 1H) 4.30 (s, 2H) 2.91 (m, 1H) 0.94-0.85 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.CN([CH:19]=[O:20])C.Cl>C1COCC1>[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH:19]=[O:20])[CH:9]=1
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(F)cc1Br
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(F)cc1C=O
Temperature: -30 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
To a solution of 2-bromo-4-fluorobenzonitrile (5.0 g, 25.0 mmol) in anhydrous THF (20 mL) is added iPrMgCl 2.01\4 in THF (15.0 mL, 30.0 mmol) at −30° C. The solution is stirred at −30° C. for 3 hours and DMF (5.80 mL, 75.0 mmol) is added. The reaction mixture is allowed to warm to room temperature and is stirred for 1 hour. The solution is cooled to −10° C., 2M hydrochloric acid (37 mL) is added and the solution is stirred for 20 minutes. The solution is concentrated in vacuo to −⅓ original volume and extracted into EtOAc (3×). The combined organics are then dried (Na2SO4), filtered and concentrated to afford 4-fluoro-2-formyl benzonitrile (3.9 g, 71%).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Br:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][NH2:41])[CH2:34][CH2:33]1>>[Br:24][C:20]1[CH:21]=[C:22]([F:23])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:27]([NH2:28])=[O:29])=[C:10]([NH:9][C:8]([NH:41][CH2:40][CH2:39][CH2:38][N:35]3[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]3)=[O:7])[S:14][N:13]=2)=[C:18]([F:26])[C:19]=1[F:25]
Reactant: CN1CCN(CCCN)CC1
Reactant: NC(=O)c1c(OCc2c(F)cc(Br)c(F)c2F)nsc1NC(=O)Oc1ccccc1
Product: CN1CCN(CCCNC(=O)Nc2snc(OCc3c(F)cc(Br)c(F)c3F)c2C(N)=O)CC1

Procedure:
The title compound was prepared from [3-(4-bromo-2,3,6-trifluoro-benzyloxy)-4-carbamoyl-isothiazol-5-yl]-carbamic acid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by the procedure analogous to Example 1. MS (APCl, m/z): 565 and 567 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10][N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:6][CH:7]=1.[C-:25]#[N:26].[K+]>CS(C)=O>[C:25]([C@@H:11]1[CH2:10][N:9]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:12]1)#[N:26]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@@H]1c1cccc(F)c1
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@@H]1c1cccc(F)c1
Temperature: 90 °C

Procedure:
A mixture of (2R,4R)-tert-butyl 2-(3-fluorophenyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (I-29) (165 mg, 0.46 mmol), potassium cyanide (36 mg, 0.55 mmol) and DMSO (2 mL) was heated at 90° C. for 3 hours. After cooling, the reaction mixture was partitioned in Et2O and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography, eluted with EtOAc/Hex (0-50% gradient) to yield (2R,4S)-tert-butyl 4-cyano-2-(3-fluorophenyl)-pyrrolidine-1-carboxylate (I-30) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.35-7.30 (m, 1 H), 7.02-6.93 (m, 2 H), 6.87 (d, J=9.6 Hz, 1 H), 5.16r1 (bs, 0.4 H), 5.00r2 (bs, 0.6 H), 4.00-3.73 (m, 2 H), 3.16 (bs, 1 H), 2.67 (bs, 1 H), 2.25-2.21 (m, 1 H), 1.49 (bs, 3 H), 1.23 (bs, 6 H). MS m/z 313.1 (M+23)+.
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:53])[CH2:20][N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([S:31]([N:34](CC4C=CC(OC)=CC=4OC)[C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)(=[O:33])=[O:32])[CH:27]=3)[CH2:22]2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:53])[CH2:20][N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([S:31]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)(=[O:32])=[O:33])[CH:27]=3)[CH2:22]2)=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccc(CN(c2ccc(F)cc2)S(=O)(=O)c2ccc3c(c2)CCN(CC(=O)c2ccc(C(C)(C)C)cc2)C3)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(C(=O)CN2CCc3cc(S(=O)(=O)Nc4ccc(F)cc4)ccc3C2)cc1
Reaction time: 2 h

Procedure:
Anisole (3 mL) was added to a solution of 2-[2-(4-tert-butylphenyl)-2-oxoethyl]-N-(2,4-dimethoxybenzyl)-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (258 mg) in chloroform (5 mL), and the mixture was cooled in ice. Trifluoroacetic acid (1 mL) was added thereto and the mixture was stirred at the same temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added thereto and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→3:2) to afford the title compound as a pale yellow amorphous substance (153 mg).
Reaction SMILES: [CH3:1][N+:2]([CH3:4])=[CH2:3].[I-].[CH3:6][C:7]1([CH3:23])[C:11]([CH3:13])([CH3:12])[O:10][B:9]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[CH:17]3)[O:8]1>CC#N.CC(O)=O>[CH3:3][N:2]([CH3:4])[CH2:1][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([B:9]3[O:10][C:11]([CH3:13])([CH3:12])[C:7]([CH3:23])([CH3:6])[O:8]3)[CH:15]=2)[NH:19][CH:18]=1
Reactant: C=[N+](C)C
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Agent: [I-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C)Cc1c[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To a suspension of Eschenmoser's salt (0.91 g, 4.9 mmol) in CH3CN (3 mL) and HOAc (1.5 mL) at rt was added a solution of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (1.0 g, 4.1 mmol) in CH3CN (3 mL) dropwise over about 10 min. After about 2 hours, the reaction was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated to give crude N,N-Dimethyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]methanamine (0.60 g, 50%); RP-HPLC (Table 1, Method g) Rt 1.39 min; 1H NMR (d6-DMSO, 400 MHz) δ11.26 (br s, 1H), 8.07 (s, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.37 (m, 2H), 3.92 (s, 2H), 2.40 (s, 6H), 1.31 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])=[CH:13][N:12]=[C:11]([C:22]([NH2:24])=[O:23])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1>ClCCl>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:3][CH:4]=3)[NH:8][C:7]=2[C:11]([C:22]([NH2:24])=[O:23])=[N:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(N)ccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3ccccc3F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
To a solution of 7-amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (25 mg, 0.078 mmol) in dichloromethane (2 mL) at rt was sequentially added methanesulfonyl chloride (22.35 mg, 0.195 mmol) and pyridine (0.016 mL, 0.195 mmol). The mixture was stirred at room temperature for 1 hr and then at 50° C. in a closed vial for 30 min. The mixture was concentrated. The residue was diluted with MeOH (1.5 mL) and subjected to prep. reverse phase HPLC purification. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution to pH 9, and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (25 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (4.81 mg, 0.012 mmol, 15.00% yield) as a pale solid. LCMS (M+H)+=399.03. 1H NMR (500 MHz, DMSO-d6) δ: 11.85 (s, 1H), 10.03 (s, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.67-7.63 (m, 2H), 7.50-7.43 (m, 2H), 7.19 (d, J=7.7 Hz, 1H), 6.92 (dd, J1=8.8 Hz, J2=2.2 Hz, 1H), 3.02 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[C:16]([CH2:18][OH:19])[CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[C:16]([CH2:18][OH:19])[CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2ccc(-c3cc(CO)cs3)s2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1csc(-c2ccc(-c3ccc(CO)s3)s2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.3 %

Procedure:
To a solution of 5-formyl-4"-hydroxymethyl-2,2':5', 2"-terthiophene (140 mg) in methanol (10 ml) was added sodium borohydride (0.1 g). The reaction mixture was stirred at room temperature for 40 minutes. Methanol was removed and water was added. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated to give light yellowish solid product (140 mg), melting point 111°-113° C.
Reaction SMILES: [C:1]([NH:4]C=C)(=[O:3])[CH3:2].[CH:7]([S:9]([O-:12])(=[O:11])=[O:10])=[CH2:8].CC(N=NC(C#N)(C)C)(C#N)C>>[CH:7]([CH2:2][C:1]([NH2:4])=[O:3])=[CH2:8].[CH:7]([S:9]([O-:12])(=[O:11])=[O:10])=[CH2:8]
Reactant: C=CNC(C)=O
Agent: C=CS(=O)(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C=CCC(N)=O
Temperature: 75 °C
Reaction time: 3 h

Procedure:
Acetamidoethylene monomer prepared in Part A (5 moles) is added to a 5 liter agitated reactor along with 2.7 moles of vinylsulfonate (sodium salt) and 16 g of AIBN. The materials are placed in a 5 liter reaction flask and heated to 75° C. while d oxygenating the flask. Temperature is increased to 80° C. and held there for 180 minutes. The reaction mixture, a solution of a copolymer of vinylacetamide and vinylsulfonate, is dissolved in water. This solution is purified by filtration and ultrafiltration in an Amicon ultrafiltration unit in the presence of added NaCl. Low molecular weight impurities are removed leaving a solution of vinylacetamide-vinylsulfonate as retentate.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14]CC)=[O:13])[C:3]1=[O:17].O.[OH-].[Li+].O.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]1=[O:17]
Reactant: CCOC(=O)c1cc2ccccc2n(C)c1=O
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(=O)c(C(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.6 %

Procedure:
2.4 g (10.4 mmol) of ethyl 1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate was dissolved in 1,4-dioxane (50 mL), and 0.65 g (15 mmol) of lithium hydroxide monohydrate and 10 mL of water were added to the solution at room temperature. The resulting mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was washed with ethyl acetate. The aqueous phase was acidified with citric acid, and then the mixture was extracted with chloroform. The organic phase was washed with water, dried, and concentrated. The residue thus obtained was washed with ethyl acetate, and thus 2.02 g (yield: 96%) of the title compound was obtained as light yellow crystals.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:19]4[S:18][N:17]=[CH:16][C:15]=4[CH:14]=[CH:13][C:12]=3[C:20]([OH:22])=O)=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CC1(C)[O:38][C@@H:37]([CH2:39][O:40][NH2:41])[CH2:36][O:35]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[OH:38][C@H:37]([CH2:36][OH:35])[CH2:39][O:40][NH:41][C:20]([C:12]1[CH:13]=[CH:14][C:15]2[CH:16]=[N:17][S:18][C:19]=2[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]=1[F:23])=[O:22]
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1ccc2cnsc2c1Nc1ccc(C2CC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOC[C@H](O)CO)c1ccc2cnsc2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
To a solution of 7-(4-cyclopropyl-2-fluoro-phenylamino)-benzo[d]isothiazole-6-carboxylic acid (155 mg, 0.47 mmol) and diisopropylethylamine (0.10 mL, 0.61 mmol) in DMF (5 mL) were added O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (97 mg, 0.66 mmol), EDCI (117 mg, 0.61 mmol) and HOBt (83 mg, 0.61 mmol). The reaction mixture was stirred for 2 hours at room temperature, diluted with ethyl acetate, washed with water, a saturated aqueous solution of sodium hydrogen carbonate, then brine before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was taken in MeOH (10 mL) and a 4.0M solution of hydrochloric acid in dioxane (1.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour before being diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate then brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to reverse-phase HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 15 to 95%, ramp time 20 minutes) to afford the title compound as a yellow solid (115 mg, 59%). LCMS (method A): RT=9.02 min, [M+H]+=418. 1H NMR (DMSO-d6, 400 MHz) 9.98 (1 H, s), 8.97 (1 H, s), 7.72 (1 H, s), 7.61 (1 H, d, J=8.35 Hz), 7.09-6.90 (3 H, m), 3.95 (1 H, dd, J=9.94, 3.81 Hz), 3.79 (2 H, d, J=16.92 Hz), 3.40 (2 H, d, J=5.46 Hz), 2.03-1.94 (1 H, m), 1.03-0.97 (2 H, m), 0.77-0.71 (2 H, m).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH:15]=O)[C:13]=2[N:14]=1>>[CH3:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([N:14]=1)=[C:12]([CH2:15][NH:2][CH3:1])[CH:11]=[CH:10][CH:9]=2
Reactant: COc1cnc2cccc(C=O)c2n1
Reactant: CN
Product: CNCc1cccc2ncc(OC)nc12

Procedure:
Methylamine (2M in THF, 5 mL) and 3-methoxy-quinoxaline-5-carbaldehyde (0.94 g, 5 mmol, prepared according to WO 2006/021448) were coupled according to method K. The title amine was isolated as a yellowish solid (0.52 g, 51% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[N:32]1[C:37]2[CH:38]=[CH:39][S:40][C:36]=2[C:35]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[N:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:44]4[CH2:45][CH2:46][N:41]([C:35]5[C:36]6[S:40][CH:39]=[CH:38][C:37]=6[N:32]=[CH:33][N:34]=5)[CH2:42][CH2:43]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1nc(N2CCNCC2)c2sccc2n1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ncnc3ccsc23)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-thieno[3,2-d]pyrimidinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=649.98 (M+H+); retention time=0.65 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[S:5][C:6]=1[C:7]([O:9]C)=O.[CH:17]([NH2:19])=O>>[N:11]1([C:4]2[S:5][C:6]3[C:7](=[O:9])[N:19]=[CH:17][NH:1][C:2]=3[N:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: NC=O
Reactant: COC(=O)c1sc(N2CCOCC2)nc1N
Product: O=c1nc[nH]c2nc(N3CCOCC3)sc12
Temperature: 150 °C
Yield: 93.2 %

Procedure:
A sealed tube was charged with methyl 4-amino-2-(4-morpholinyl)-1,3-thiazole-5-carboxylate (4 g, 16.44 mmol) and formamide (40 mL, 1004 mmol). The reaction was heated at 150° C. overnight. The reaction mixture was cooled, filtered, and the solid was washed with DCM and MeOH. The solid was collected and dried under vacuum to give 3.65 g (93%) of product. LCMS (ES) m/z=239.0 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δppm 12.4 (br s, 1H, NH), 8.10 (s, 1H) 3.72 (m, 4H). 3.58 (m, 4H).