Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:16]=[C:17](Cl)[C:18]([F:20])=[CH:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([F:20])=[CH:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2cc(F)c(-c3ccccc3)nc2C=Cc2ccccc21
Yield: 88.4 %

Procedure:
The title compound (20.1 mg, 88.5%) was prepared from 1D (20.0 mg, 0.066 mmol) and phenylboronic acid (12.1 mg, 0.099 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=3.326 min; LCMS Found: (M+H)+=345.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][C@@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:24]([OH:26])=O.[NH3:27]>>[CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][C@@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:24]([NH2:27])=[O:26]
Reactant: N
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@@H]3CCOC3)c12
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@@H]3CCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 5-methyl-4-{2-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-ylamino}-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]O)=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1.N1C=CC=CC=1.C(Cl)[Cl:25]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][Cl:25])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: ClCCl
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCO
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)ccc1CCCl
Temperature: 0 °C
Yield: 98 %

Procedure:
12 g thionyl chloride (7.4 ml, 100 mmol) in 10 ml toluene (abs.) are quickly added in a drop-wise manner to a solution of 6.78 g 2-(4-chloro-2-nitrophenyl)ethanol (33 mmol) in 100 ml abs. toluene and 2.5 ml pyridine. This is heated 2 h under reflux, cooled, poured onto 100 g ice and mixed with 100 ml CH2Cl2. The aqueous phase is extracted 2× each with 50 ml CH2Cl2. The combined organic phases are neutralized 2× each with 80 ml saturated bicarbonate solution, dried over Na2SO4, filtered and rotary evaporated. 7.12 g (32 mmol, 98%) 2-(4-chloro-2-nitrophenyl)ethyl chloride are obtained as a brown oil which hardens to a brown solid after some days in the refrigerator.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.I[CH2:16][C:17](=[O:39])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C:32](=[CH:33][CH2:34]2)[C@:30]2([CH3:31])[C:25](=[CH:26][C:27](=[O:37])[CH:28]=[CH:29]2)[CH2:24][CH2:23]3)[CH2:20][C@H:19]1[CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:16][C:17](=[O:39])[C@@H:18]3[C@:35]4([CH3:36])[C@H:21]([C@H:22]5[C:32](=[CH:33][CH2:34]4)[C@:30]4([CH3:31])[C:25](=[CH:26][C:27](=[O:37])[CH:28]=[CH:29]4)[CH2:24][CH2:23]5)[CH2:20][C@H:19]3[CH3:38])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CI
Product: COc1ccc(N2CCN(CC(=O)[C@H]3[C@H](C)C[C@H]4[C@@H]5CCC6=CC(=O)C=C[C@]6(C)C5=CC[C@@]43C)CC2)cc1

Procedure:
Following the general procedure of EXAMPLES 1-6A, 7, 8, 11-19, 83, 126 and 139 and making non-critical variations but starting with 4 -(4-methoxyphenyl)piperazine (PREPARATION A-31) and 21-iodo-16αmethylpregna-1,4,9(11)-triene-3,20-dione (PREPARATION S-22), the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][C:16]([CH2:24][OH:25])([CH2:17]4)[CH2:15]2)[CH2:21]3)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CO.[CH2:28](N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][C:16]([CH2:24][OH:25])([CH2:17]4)[CH2:15]2)[CH2:21]3)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:28])=[O:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(CO)(C4)C2)C3)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cc(Cl)c(OCC23CC4CC(CC(CO)(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.7 %

Procedure:
A solution of 5-chloro-2-fluoro-4-((3-(hydroxymethyl)adamantan-1-yl)methoxy)benzoic acid (3.53 g, 9.57 mmol), 4-dimethylaminopyridine (0.23 g, 1.90 mmol), and methanol (3.87 mL, 95.70 mmol) in anhydrous dimethylformamide (50 mL) under nitrogen was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (3.67 g, 19.10 mmol). The reaction mixture was stirred for 24 hours at ambient temperature; diluted with ethyl acetate (200 mL) and washed with water (100 mL), saturated ammonium chloride (100 mL), and brine (100 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (3:1 hexanes:ethyl acetate) to provide the title compound (0.65 g, 18%): 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J=7.9 Hz, 1H), 6.59 (d, J=12.6 Hz, 1H), 3.85 (s, 3H), 3.56 (s, 2H), 3.23 (s, 2H), 2.11 (br s, 1H), 1.74-1.40 (m, 14H); MS (ES+) m/z 383.1, 385.1 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:23])[C:9]1[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:10]=1[O:21][CH3:22].Br[CH2:25][CH2:26][O:27][CH2:28][CH2:29]Br>>[CH3:22][O:21][C:10]1[CH:11]=[C:12]([C:17]([F:19])([F:20])[F:18])[CH:13]=[C:14]([S:15][CH3:16])[C:9]=1[C:8]([NH:7][CH:3]1[CH2:4][CH2:5][CH2:6][CH:2]1[N:1]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Reactant: BrCCOCCBr
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCOCC1

Procedure:
The title compound, white solid, MS: m/e=419.1 [(M+H)+], was prepared in accordance with the general method of example 10 from N-((1RS,2SR)-2-amino-cyclopentyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate O) and bis(2-bromoethyl)ether.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:20]=1[NH2:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([NH:21][C:20]3[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:19]=3[Cl:18])=[O:17])=[CH:13][N:14]=2)[CH:3]=1
Reactant: Cc1cccc(Cl)c1N
Reactant: Cc1nc(Br)cc(Nc2ncc(C(=O)O)s2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(Br)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formic acid (Compound 12) (31.5 g, 0.1 mol), DMF (630 mL) and 2-chloro-6-methylaniline (Compound 8) (17.0 g, 0.12 mol) were mixed in a reaction flask, and then HATU (45.6 g, 0.2 mol) and triethylamine (25.3 g, 0.25 mol) was added when controlling the temperature at 20° C. Then the mixture reacted by stirring at room temperature overnight. After that water (3150 mL) was added and stirred for 30 min and then filtrated. The cake was dried to give target Compound 14 (31.2 g, yield: 71.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9](C1C=CC=C(C2C=CC(CC3C(CCCC)=NN4CCCCC=34)=CC=2)C=1C([O-])=O)(C)[CH3:10].BrCC(=O)C>CC(C)=O>[CH3:10][C:9]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:8]=1
Reactant: Nc1ccccn1
Reactant: CCCCc1nn2c(c1Cc1ccc(-c3cccc(C(C)(C)C)c3C(=O)[O-])cc1)CCCC2
Agent: CC(=O)CBr
Solvent: CC(C)=O
Product: Cc1cn2ccccc2n1
Yield: 245.4 %

Procedure:
A mixture of 5 g of 2-amino pyridine and 250 ml of acetone were added at ambient temperature to a mixture of 7.25 g of 1 bromo 2-propanone and 20 ml of acetone and the mixture was refluxed for 30 minutes. Using the procedure of Stage C of Example 22, 5.3 g of the expected product were obtained in the form of an orange oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[NH:21][N:20]=2)COCC[Si](C)(C)C)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41]([NH2:43])=[O:42].N1C2C(=CC=CC=2)C=N1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(Cl)Cl.O.CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[N:21]([CH2:37][C:38]3[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=3)[C:41]([NH2:43])=[O:42])[N:20]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COc1cccc2[nH]nc(N(COCC[Si](C)(C)C)S(=O)(=O)c3ccc(Cl)s3)c12
Reactant: NC(=O)c1cccc(CCl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C(N)=O)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 5-chloro-N-[4-(methyloxy)-1H-indazol-3-yl]-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2-thiophenesulfonamide (for a preparation see Intermediate 8) (150 mg, 0.316 mmol) into DMF (2 mL) was added at ambient temperature potassium carbonate (87 mg, 0.63 mmol) and 3-(chloromethyl)benzamide (Maybridge) (64.4 mg, 0.380 mmol). The resulting mixture was stirred at 50° C. overnight, and then diluted with DCM (2 mL) and water (2 mL). The organic mixture was partitioned and the aqueous layer was further extracted with 2 mL of DCM. The organic solutions were combined together, dried over an hydrophobic frit and evaporated under a nitrogen stream in a blowdown unit. The crude product was judged by LCMS to be pure enough to be engaged in the next step without any further purification. LCMS (System A) RT=1.37 min, ES+ve m/z 607/609 (M+H)+. In a 2 to 5 mL Biotage microwave vial were added the crude indazole product and TBAF solution in THF (1M, 3.16 mL, 3.16 mmol). The reaction vessel was sealed and heated in a Biotage Initiator at 110° C. for 10 min (very high absorption level). The crude mixture was then diluted with 2 mL of DCM and 2 mL of water. The organic layer was separated and the aqueous layer was further extracted with 2 mL of DCM. The combined organic solutions were dried over an hydrophobic frit, and evaporated under a nitrogen stream in a blowdown unit. The residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents NB (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was removed under a stream of nitrogen in a Radleys blowdown apparatus to give the title compound (76 mg, 50%). LCMS (System A) RT=0.97 min, ES+ve m/z 477/479 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)=[O:4]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1cc(-c2ccccc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCn1nc(-c2ccccc2)cc1C(=O)OC
Temperature: 60 °C

Procedure:
5-Phenyl-2H-pyrazole-3-carboxylic acid methyl ester (9.10 g, 45.0 mmol) is taken up in 100 mL acetonitrile and heated to 60° C. Ethyl 4-bromobutanoate (8.78 g, 45.0 mmol) and potassium carbonate (8.09 g, 58.5 mmol) are added and the reaction mixture is heated to 85° C. and stirred under reflux for 5 h. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in water and extracted with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash column chromatography (silica gel, 8-40% ethyl acetate in heptane). Yield: 10.3 g. Rf (silica gel, 2% methanol in DCM)=0.41.
Reaction SMILES: C=O.[CH3:3]S(O)(=O)=O.[Cl:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][NH:12][CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.[OH-].[Na+].Cl>CN(C)C=O.C(O)C>[ClH:8].[Cl:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][N:12]1[CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][C:19]=2[CH2:3]1
Reactant: CS(=O)(=O)O
Reactant: Clc1ccccc1CNCCc1cccs1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 20 °C
Yield: 146.4 %

Procedure:
To 2.25 g (0.075 M) paraformaldehyde suspended in 20 ml dimethylformamide are added 9.61 g (0.1 M) methanesulfonic acid. The medium being at a temperature of 72° C., 13 g (0.05 M) N-(2-chloro-benzyl)-2-(2-thienyl)ethylamine dissolved in 5 ml dimethylformamide are added over 2 minutes. The temperature of the reaction medium reaches 90° C. The reaction medium is then cooled to 20° C. and poured over 50 ml 4N sodium hydroxide. The material is extracted with 1×30 ml and then 1×20 ml methylene chloride. The organic phases are combined, dried over sodium sulfate and evaporated, to give an oil which is taken up into 30 ml ethanol in which are dissolved 0.15 mole gaseous hydrochloric acid. After partial evaporation of the ethanol, the desired product precipitates out. It is filtered, washed with acetone and dried, to give 11.35 g 5-(2-chloro-benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (Yield: 75.6%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][C:6]=1[C:29]1[C:33]([CH3:34])=[CH:32][O:31][N:30]=1)=[O:4].Cl[C:36]1[CH:45]=[CH:44][C:43]2[CH2:42][CH2:41][N:40]3[C:46]4[CH:47]=[CH:48][CH:49]=[C:50]([F:53])[C:51]=4[CH:52]=[C:39]3[C:38]=2[N:37]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.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.[Pd].[Pd]>[F:53][C:50]1[C:51]2[CH:52]=[C:39]3[C:38]4[N:37]=[C:36]([C:11]5[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][C:8]6[O:7][C:6]([C:29]7[C:33]([CH3:34])=[CH:32][O:31][N:30]=7)=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[C:9]=6[CH:10]=5)[CH:45]=[CH:44][C:43]=4[CH2:42][CH2:41][N:40]3[C:46]=2[CH:47]=[CH:48][CH:49]=1
Reactant: CNC(=O)c1c(-c2nocc2C)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2nocc2C)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 85 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a mixture of N-methyl-2-(4-methylisoxazol-3-yl)-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (60 mg, 0.12 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, 0.18 mmol) and K3PO4.3H2O (98 mg, 0.37 mmol) in dioxane/H2O (1.5 mL/0.5 mL) was added Pd2(dba)3 (8 mg, 0.008 mmol) and X-Phos (8 mg, 0.016 mmol) under N2. The mixture was stirred at 85° C. for 3 h. It was concentrated, diluted with water, extracted with EtOAc, and dried over Na2SO4. The residue was purified by prep-TLC (DCM:MeOH=60:1) to get the product (35 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 9.12 (d, J=3.6 Hz, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 7.76 (s, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.28˜7.26 (m, 1H), 7.21˜7.12 (m, 2H), 6.85˜6.75 (m, 1H), 4.36 (t, J=6.4 Hz, 2H), 3.46 (s, 3H), 3.33 (t, J=6.4 Hz, 2H), 3.03 (d, J=4.8 Hz, 3H), 2.60 (s, 3H), 2.40 (s, 3H). MS (M+H)+: 600.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[S:5][C:6]=1[CH3:7].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C=O)cc1Br
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1sc(CO)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A solution of the compound (1.00 g) obtained in Example 126a in ethanol (20 mL) was cooled in an ice bath, and sodium borohydride (0.28 g) was added. The reaction mixture was stirred at room temperature for 1 hr and cooled in an ice bath. Aqueous saturated ammonium chloride was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous saturated ammonium chloride and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.79 g) as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:14][C:13]([NH:15][CH3:16])=[N:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[I:19]I.S(=O)(O)[O-].[Na+]>CN(C=O)C>[I:19][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]3[S:14][C:13]([NH:15][CH3:16])=[N:12][N:11]=3)[CH:5]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: CNc1nnc(-c2ccc3[nH]ccc3c2)s1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nnc(-c2ccc3[nH]cc(I)c3c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
To a solution of 5-(1H-indol-5-yl)-N-methyl-1,3,4-thiadiazol-2-amine (0.5 g, 2.17 mmol) in DMF (5 mL) was added KOH (0.135 g, 2.39 mmol) followed by I2 (0.6 g, 2.39 mmol). The mixture was stirred at RT for 2 h and 10% aq sodium bisulphite (2.5 mL) solution was added. The resulting precipitate was filtered and washed with H2O, dried to give 5-(3-iodo-1H-indol-5-yl)-N-methyl-1,3,4-thiadiazol-2-amine (0.3 g, 39%). MS (ESI, pos. ion) m/z: 357 (M+1); 1HNMR (DMSO-d6, 300 MHz): δ ppm 2.9 (s, 3H), 7.7 (m, 4H), 11.8 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Li+].Cl>O1CCCC1.O.CO.C(Cl)(Cl)Cl.O>[CH:21]1([S:18]([C:15]2[CH:14]=[CH:13][C:12]([CH:5]([CH2:6][CH:7]3[CH2:8][CH2:9][CH2:10][CH2:11]3)[C:4]([OH:26])=[O:3])=[CH:17][CH:16]=2)(=[O:19])=[O:20])[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)C2CCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
A solution of 2-(4-cyclopentanesulfonyl-phenyl)-3-cyclopentyl-propionic acid ethyl ester (160 mg, 0.42 mmol) in tetrahydrofuran/water/methanol (1.05 mL, 3:1:1) was treated with a 1N aqueous lithium hydroxide solution (0.85 mL, 0.85 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with chloroform (30 mL) and water (50 mL), acidified to pH=1 with a 1N aqueous hydrochloric acid solution, and extracted with a solution of chloroform/methanol (90/10, 3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 chloroform/methanol) afforded 2-(4-cyclopentanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (101.9 mg, 68.7%) as an off white solid: mp 165-167° C.; FAB-HRMS m/e calcd for C19H26O4S (M+H)+ 351.1630 found 351.1646.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[CH:10]=[C:4]2[CH2:3]1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=1.C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.[Pd].[Pd].O1CCOCC1>[Br:19][C:17]1[CH:18]=[C:13]([NH:11][C:9]2[CH:10]=[C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][N:5]3[N:8]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CN1CCn2nc(N)cc2C1
Agent: [Pd]
Agent: C1=c2ccccc2=C(c2cccc3ccccc23)C(P(c2ccccc2)c2ccccc2)(P(c2ccccc2)c2ccccc2)C1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Temperature: 110 °C
Yield: 16.8 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 113e (1.02 g, 6.7 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (2.15 g, 8.1 mmol), Pd2(dba)3 (610 mg, 0.67 mmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (775 mg, 1.34 mmol), cesium carbonate (4.37 g, 13.6 mmol), and 1,4-dioxane (30 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (15:1, V/V) to afford 113f (380 mg, 14%) as a white solid. LCMS: [M+H]+ 338
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[C:5]1([S:11]([C:14]2[CH:23]=[CH:22][C:17]3[NH:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>ClCCl>[C:5]1([S:11]([C:14]2[CH:23]=[CH:22][C:17]3[N:18]([C:1]([Cl:4])=[O:2])[CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cl)N1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
To a solution of phosgene (1.44 mL of a 1.8 M solution in dichloromethane, 2.64 mmol) at 0° C. was added a solution of 7-benzenesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (0.663 g., 2.4 mmol) in 3 mL dichloromethane followed by dropwise addition of triethylamine (0.361 mL, 2.6 mmol) over three minutes. The reaction was allowed to warm to room temperature and was stirred for an hour. The reaction mixture was then concentrated in vacuo, and then dissolved in 50 mL dichloromethane which was removed in vacuo. A suspension of the crude residue in 60 mL of 1:1 ethyl ether: hexanes was washed with 3 times with 50 mL of 6N aqueous hydrogen chloride. The organic fractions were dried over MgSO4 and concentrated in vacuo to give 7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl chloride, which was used directly in the following step.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][C:31](=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:39]COCC>>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][CH:31]([OH:37])[CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][CH3:36])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCC(=O)C=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CCOCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: CCCCC(C)C(O)C=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture obtained by adding 0.1 g of lithium aluminum hydride to 20 ml of ether was added 0.55 g of 1-(3,4-dibenzyloxyphenyl)-1-octen-3-one under ice-cooling and the mixture was stirred for one hour at room temperature. To the reaction mixture was gradually added 10 ml of an aqueous 10% hydrochloric acid solution and the ether layer was collected, washed with water, and concentrated under reduced pressure to provide a solid product. By washing the product with a mixture of ether and n-hexane (1:3), 0.4 g of 1-(3,4-dibenzyloxyphenyl)-4-methyl-1-octen-3-ol was obtained.