Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[CH2:12][N:11]([C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[C:10]1=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[CH2:12][N:11]([C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[C:10]1=[S:40])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@@H]2O[Si](C)(C)C(C)(C)C)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@@H]2O[Si](C)(C)C(C)(C)C)CC1
Yield: 88 %

Procedure:
3-(R)-Tert-butyldimethylsilyloxy-4-(S)-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]-2-pyrrolidone was dissolved in dry benzene (200 ml), and the solution was mixed with Lawesson's reagent (4.49 g, 11.1 mmol) and heated under reflux for 3 hours. After cooling, benzene was evaporated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=4:1, to thereby obtain 7.96 g (88%) of the title compound as a light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].OO.[O-:13]Cl=O.[Na+].[O-]S([O-])=O.[Na+].[Na+].Cl>O>[N+:1]([C:4]1[S:8][C:7]([C:9]([OH:13])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: O=S([O-])[O-]
Agent: OO
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 500 mL round bottomed flask with a stirring bar, was added 5-nitrothiophene-2-carboxaldehyde (7.86 g, 50.00 mmol) in CH13CN (50 mL), NaH2PO4 (1.86 g, 13.50 mmol) in water (20 mL), and 30% H2O2 (aq) (6 mL). To this mixture, cooled in an ice bath, was added NaClO2 (8 g, 70.80 mmol) in water (70 mL) dropwise over a period of an hour. The reaction was stirred at room temperature for 5 hours. It was worked up by addition of Na2SO3 (500 mg), acidified with 1M HCl, and then extracted with ethyl acetate (3×). The combined organic layers were washed with water (1×), and brine (1×). Drying (MgSO4), filtration and removal of the solvents in vacuo yielded 5-Nitrothiophene-2-carboxylic acid as a yellow powder.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH:12]=[C:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH:12]=[C:13]([CH2:14][C:15]([OH:17])=[O:16])[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of biphenyl imidazolyl tert-butyl ester (0,039 mmol, the title compound of Example 1445) in 0.5 mL of chloroform is added 0.25 mL of TFA, and the progress of the reaction is monitored by 1H NMR. The resulting solution is stirred at room temperature until the reaction is complete. The mixture is quenched with methanol and concentrated in vacuo. The residue is purified to give the title compound of Example 1446.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][C:7]=1[F:14]>>[N:1]([CH2:10][C:9]1[CH:12]=[CH:13][C:6]([Br:5])=[C:7]([F:14])[CH:8]=1)=[N+:2]=[N-:3]
Reactant: Fc1cc(CBr)ccc1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCc1ccc(Br)c(F)c1
Temperature: 90 °C
Yield: 95.5 %

Procedure:
Add sodium azide (2.912 g, 44.8 mmol) to a solution of 4-bromo-3-fluorobenzyl bromide (6 g, 22.4 mmol) in anhydrous DM (127 mL) at room temperature under nitrogen. Heat the mixture at 90° C. for 1 h. Concentrate in vacuo and partition the residue between water and EtOAc. Extract the aqueous phase twice with EtOAc. Wash the combined organics extracts with iced-water. Dry the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a solid (4.92 g, 96%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].CCN(C(C)C)C(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:4]1[CH:3]=[C:2]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][C:16]=2[N+:25]([O-:27])=[O:26])[CH:7]=[CH:6][CH:5]=1)[CH3:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=O)Cc1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1
Temperature: 130 °C
Yield: 17 %

Procedure:
Ethyl 2-(3-iodophenyl)acetate (0.500 g, 1.72 mmol), 4-bromo-3-nitrobenzotrifluoride (1.86 g, 6.89 mmol commercially available), tetrabutylammonium chloride (0.527 g, 1.90 mmol), i-Pr2NEt (0.33 mL, 1.90 mmol) and Pd(OAc)2 (0.039 g, 0.17 mmol) were combined neat in a sealed vial and heated at 130° C. for 65 h. The cooled reaction mixture was applied directly to silica gel and eluted with 25% EtOAc/hexanes to provide 2′-nitro-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-acetic acid ethyl ester (0.107 g, 17% yield). MS (ESI) m/z: 354.0 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:8][N:7]1[C:3]([CH2:2][N:21]2[CH2:26][CH2:25][N:24]([CH2:2][C:3]3[N:7]([CH3:8])[N:6]=[C:5]([C:9]4[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=4)[CH:4]=3)[CH2:23][CH2:22]2)=[CH:4][C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:6]1
Reactant: C1CNCCN1
Reactant: COc1cc(-c2cc(CCl)n(C)n2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)nn4C)CC3)n(C)n2)cc(OC)c1OC

Procedure:
5-Chloromethyl-1-methyl-3-(3,4,5-trimethoxy-phenyl)pyrazole (119 mg) and piperazine (17 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[C:6]([CH:16]=O)[N:5]=[C:4]2[C:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([F:29])[CH:22]=3)=[N:19][O:20][C:3]=12.[NH:30]1[C:37](=[O:38])[CH2:36][C:34](=[O:35])[NH:33][C:31]1=[O:32]>C(O)(C)C>[Cl:1][C:2]1[C:3]2[O:20][N:19]=[C:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([F:29])[CH:22]=3)[C:4]=2[N:5]=[C:6]2[C:7]=1[N:8]1[CH2:9][C@@H:10]([CH3:15])[O:11][C@@H:12]([CH3:14])[C@@H:13]1[C:36]1([C:34](=[O:35])[NH:33][C:31](=[O:32])[NH:30][C:37]1=[O:38])[CH2:16]2
Reactant: C[C@@H]1CN(c2c(C=O)nc3c(-c4ccc(C#N)c(F)c4)noc3c2Cl)C[C@H](C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Product: C[C@@H]1CN2c3c(nc4c(-c5ccc(C#N)c(F)c5)noc4c3Cl)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 80 °C
Yield: 26 %

Procedure:
To isopropanol (20 ml) was added to 4-(7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)-5-formylisoxazolo[4,5-b]pyridin-3-yl)-2-fluorobenzonitrile (Intermediate 416, 0.126 g, 0.30 mmol) and barbituric acid (0.039 g, 0.30 mmol). The mixture was heated to 80° C. for about 2 days. The mixture was concentrated, and the residue was purified by chromatography on silica using 20% acetone in n-hexane. The solids obtained were triturated with methanol gave 41 mg of product.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:28]=[CH:27][C:20]3[S:21][C:22]([C:24](O)=[O:25])=[CH:23][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.C[O:39][C:40](=[O:43])[CH2:41][NH2:42]>CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:28]=[CH:27][C:20]3[S:21][C:22]([C:24]([NH:42][CH2:41][C:40]([OH:39])=[O:43])=[O:25])=[CH:23][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2sc(C(=O)O)cc2c1
Reactant: COC(=O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2sc(C(=O)NCC(=O)O)cc2c1
Yield: 42.9 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carboxylic acid (310 mg, 0.686 mmol), DMAP (167 mg, 1.37 mmol), EDC (197 mg, 1.03 mmol), and glycine methyl ester hydrochloride (172 mg, 1.37 mmol) are reacted and hydrolyzed in a sequence analogous to Example 5 to afford the title compound (150 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](OC2C=NC(Cl)=CC=2)=[N:6][CH:7]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Reactant: Clc1ccc(Oc2ncc(Br)cn2)cn1
Product: CC(=O)NC(C)CCc1ccc(Oc2ncc(Br)cn2)cc1

Procedure:
5-Bromo-2-(6-chloropyridin-3-yloxy)pyrimidine (500 mg, 1.745 mmol) and N-[3-(4-hydroxyphenyl)-1-methylpropyl]acetamide (362 mg, 1.745 mmol) were reacted in analogy to example 2c. Yield: 509 mg (80%), M+H+: 364.03.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+2]>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[O:17])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a solution of 4-(2-benzyloxybenzyl)benzyl alcohol (1.0 g) in dichloromethane (50 mL) was added manganese (II) oxide (10 g), and the mixture was stirred at room temperature for 3 hours. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give 4-(2-benzyloxybenzyl)benzaldehyde (0.97 g).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:2].S(Cl)([Cl:15])=O.CN(C)C=O>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C#N)ccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1C(=O)Cl
Yield: 100 %

Procedure:
To a solution of A-4 (4-cyano-2-methylbenzoic acid) (20 g, 0.124 mol) in toluene (200 mL) was added thionyl chloride (18 mL, 0.248 mol), and catalytic amount of dimethylformamide (0.5 mL). The resultant mixture was stirred at 70° C. for 14 h, and concentrated under reduced pressure to give A-5 (4-cyano-2-methylbenzoyl chloride) (24 g, yield 100%), which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([C:12]([O:15][C:16](=[C:18]([F:20])[F:19])[F:17])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[F:7])([F:4])([F:3])[F:2].[CH:21]([OH:24])([CH3:23])[CH3:22]>>[C:1]([O:5][C:6]([C:12]([O:15][CH:16]([C:18]([C:21]([OH:24])([CH3:23])[CH3:22])([F:19])[F:20])[F:17])([F:13])[F:14])([C:8]([F:11])([F:10])[F:9])[F:7])([F:4])([F:3])[F:2]
Reactant: CC(C)O
Reactant: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)F)C(F)(F)F
Product: CC(C)(O)C(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)F)C(F)(F)F

Procedure:
CF3OCF(CF3)CF2OCFHCF2C(CH3)2OH was prepared by the reaction of CF3OCF(CF3)CF2OCF═CF2 (52.9 g, 0.16 mol) with isopropanol (202 g, 3.37 mol) using LUPEROX 575 (11.4 g) as free radical initiator at 75° C. The resulting product reaction mixture was distilled and the distillation fraction of b.r.=161-166° C. used in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:15])[C:8](=[N:13]O)[C:9](=[O:12])[CH2:10][CH3:11])=[CH:3][CH:2]=1.[H][H].Cl>C(O)(=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:15])[CH:8]([NH2:13])[C:9](=[O:12])[CH2:10][CH3:11])=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CCC(=O)C(=NO)C(=O)c1ccncc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CCC(=O)C(N)C(O)c1ccncc1

Procedure:
In 1000 ml acetic acid was dissolved 23.0 g (0.11 mol) of 1-(4-pyridyl)-1,3-diketo-2-oximinopentane. The solution is charged with 1.0 g of 10% palladium on carbon and hydrogenated until three equivalents of hydrogen were taken up. The mixture was acidified with 18.5 ml of 12N hydrochloric acid, filtered and the solvent evaporaed to give the title compound as the dihydrochloric acid salt; m.p. 225° C.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][C@H:3]1[O:18][C:19]1[N:24]=[C:23]([O:25]CC2C=CC(OC)=CC=2)[CH:22]=[C:21]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([C:44]4[S:45][CH:46]=[CH:47][N:48]=4)[CH:42]=3)[N:37](C3CCCCO3)[N:36]=2)[N:20]=1.[C:55]([OH:61])([C:57]([F:60])([F:59])[F:58])=[O:56]>>[F:58][C:57]([F:60])([F:59])[C:55]([OH:61])=[O:56].[F:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[O:18][C:19]1[NH:24][C:23](=[O:25])[CH:22]=[C:21]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([C:44]4[S:45][CH:46]=[CH:47][N:48]=4)[CH:42]=3)[NH:37][N:36]=2)[N:20]=1
Reactant: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(-c5nccs5)cc34)nc(O[C@@H]3CN(C(=O)OCc4ccccc4)CC[C@H]3F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(-c2n[nH]c3ccc(-c4nccs4)cc23)nc(O[C@@H]2CNCC[C@H]2F)[nH]1
Temperature: 100 °C
Yield: 15 %

Procedure:
A glass microwave reaction vessel was charged with benzyl trans-4-fluoro-3-((4-((4-methoxybenzyl)oxy)-6-(1-(tetrahydro-2H-pyran-2-yl)-5-(thiazol-2-yl)-1H-indazol-3-yl)pyrimidin-2-yl)oxy)piperidine-1-carboxylate (racemic) (200 mg, 0.26 mmol) and TFA (2 mL). The reaction was stirred and heated in a microwave reactor at 100° C. for 30 min, then cooled to RT. The solvent was removed and the residue was purified with preparative HPLC (20-100% MeCN in water with 0.1% TFA) to give 2-((trans-4-fluoropiperidin-3-yl)oxy)-6-(5-(thiazol-2-yl)-1H-indazol-3-yl)pyrimidin-4(3H)-one trifluoroacetate (racemic) (20 mg, 15%) as a off white solid. MS (ESI, pos. ion) m/z: 412.8 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 13.90 (s, 1 H), 8.96 (brs, 3 H), 8.07 (d, 1 H, J=9.2 Hz), 7.95 (t, 1 H, J=2.4 Hz), 7.75-7.79 (m, 2 H), 5.63 (s, 1 H), 5.05-5.20 (m, 1 H), 3.70-3.72 (m, 1 H), 3.28-3.40 (m, 1 H), 3.16-3.23 (m, 2 H), 2.15-2.30 (m, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.[O:12]1[CH2:14][CH2:13]1>CCOCC>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:14][CH2:13][OH:12])[S:4][CH:3]=1
Reactant: C1CO1
Reactant: Cc1ccsc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1csc(CCO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of 3-methylthiophene (5 g, 51.0 mmol) in dry ether (250 mL) at −65° C. was added n-BuLi (25 mL, 2.5 N in THF) dropwise. After stirring for 1 h, oxirane (2.7 g, 61.3 mmol) was added in one portion. The resulting reaction mixture was warmed to room temperature and stirred overnight. The reaction was then quenched with water. After separation of layers, the organic layer was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (6.2 g, 86%).
Reaction SMILES: [S:1]1(=[O:15])(=[O:14])[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[C:3](=[O:13])[NH:2]1.Cl[CH2:17][C:18](=[O:20])[CH3:19]>CS(C)=O>[CH2:17]([N:2]1[C:3](=[O:13])[C:4]2[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]=2[S:1]1(=[O:15])=[O:14])[C:18]([CH3:19])=[O:20]
Reactant: CC(=O)CCl
Reactant: O=C1NS(=O)(=O)c2c1[nH]c1ccccc21
Solvent: CS(C)=O
Product: CC(=O)CN1C(=O)c2[nH]c3ccccc3c2S1(=O)=O

Procedure:
The starting compounds of the formula VI can, for example, be obtained from an alkali metal salt of a 2H-isothiazolo[4,5-b]-indole-3(4H)-one-1,1-dioxide of the formula Xa by reaction with a halo-acetone, such as chloroacetone, in dimethylsulfoxide and at a temperature of 100° to 150° C., to form a corresponding 2-acetonyl-2H-isothiazolo[4,5-b]indol-3(4H)-one-1,1-dioxide. This compound is then subjected to a base-catalyzed rearrangement reaction in the presence of 2 to 3 equivalents of an alkali metal alcoholate, which yields a 3-acetyl-2,5-dihydro-4-hydroxy-1,2-thiazino[5,6-b]-indole-1,1-dioxide of the formula ##STR12## wherein R2 and Y have the meanings defined above.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH:14][CH2:15][C:16]2([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=1)(=O)=O.[Cl:26][C:27]1[C:28](B(O)O)=[CH:29][C:30]([F:33])=[N:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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].C(Cl)Cl>[Cl:26][C:27]1[C:28]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH:14][CH2:15][C:16]3([C:22]#[N:23])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:8]=2)=[CH:29][C:30]([F:33])=[N:31][CH:32]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: N#CC1(CNc2nc(OS(=O)(=O)C(F)(F)F)ccc2F)CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: N#CC1(CNc2nc(-c3cc(F)ncc3Cl)ccc2F)CCOCC1
Temperature: 110 °C
Yield: 78.8 %

Procedure:
A mixture of 5-fluoro-6-((4-cyano-tetrahydro-2H-pyran-4-yl)methylamino)pyridin-2-yl trifluoromethanesulfonate (200 mg, 0.522 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (183.2 mg, 1.044 mmol), PdCl2(dppf)-CH2Cl2 adduct (85.1 mg, 0.104 mmol), and SODIUM CARBONATE (221.6 mg, 2.08 mmol, in 1 ml of water) in DME (3 ml) was de-gassed and heated at 110° C. for 20 min in a sealed microwave vial, cooled. The upper layer of mixture was separated, the bottom one was extracted with ethyl acetates, the organic layers were combined and concentrated to afford the crude product, which was purified by ISCO (10 to 50% ethyl acetate in heptane, 20 min) to afford 150 mg (79% yield) of the desired product was an off-white solid. LCMS (m/z): 365.1 [M+H]+; retention time=0.929 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=O)C.[OH-].[NH4+:13]>>[NH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([NH2:13])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1csc(N)n1
Yield: 69 %

Procedure:
A solution of 2-amino-thiazole-4-carboxylic acid ethyl ester (258 mg, 1.5 mmol) (prepared as described in example 3, step 1) in concentrated aqueous ammonium hydroxide was heated to reflux for 8 hours. The reaction mixture was concentrated to dryness and residual water removed by azeotropic distillation with toluene. The residue was purified by chromatography over silica gel eluted with 2% v/v methanol in ethyl acetate to give 2-amino-thiazole-4-carboxylic acid amide as a colorless solid (149 mg, 69%).
Reaction SMILES: [CH3:1]I.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2>CN(C)C=O>[CH3:1][N:14]1[C:15]2[C:11](=[C:10]([CH3:9])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: CI
Reactant: Cc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1ccn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
Methyl iodide (28.44 g) and cesium carbonate (82.26 g) were added to a solution of 4-methylindole (22.08 g) in dimethylformamide (200 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered with Celite (trade name), and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride was added to the obtained residue, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and a saturated salt solution, and concentrated under reduced pressure after drying with anhydrous sodium sulfate. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=100:0→85:15) to give the title compound (20.83 g) having the following physical data.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=[N:53][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CCCC1>CN(C=O)C>[CH:48]1([NH:53][C:30](=[O:32])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([C:10]3[C:11]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[C:12]=4[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:36][CH3:37])[CH2:1][CH3:2])[N:9]=3)[CH:28]=2)[CH2:49][CH2:50][CH2:51][CH2:52]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NC3CCCC3)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.4 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and cyclopentanamine (8.91 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (6.0 mg, 17%).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH:17]([CH:19]1[CH2:23][CH2:22][N:21](C(OCC2C=CC=CC=2)=O)[CH2:20]1)=O.O>O1CCCC1>[NH:21]1[CH2:22][CH2:23][CH:19]([CH2:17][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:20]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)C1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCC1CCNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (15.9 g) in tetrahydrofuran (200 mL) was added sodium hydride (60% in oil, 2.88 g) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added benzyl 3-formylpyrrolidine-1-carboxylate (15.0 g) and the mixture was stirred for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was dissolved in methanol (500 ml), palladium hydroxide/carbon (2.0 g) was added, and the mixture was stirred under a hydrogen atmosphere (3 atm) at 40° C. for 4 hr. The reaction solution was allowed to cool to room temperature, the reaction system was substituted by nitrogen, filtered, and the solvent was evaporated to give the title compound (8.0 g, yield 73%) as a colorless oil.