Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=S)=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1.[NH3:29]>>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[NH:29])=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1
Reactant: N
Reactant: Cc1ccc(OCc2c(F)cccc2Cl)c(NC(=S)Nc2ccc(Cl)cc2)n1
Product: Cc1ccc(OCc2c(F)cccc2Cl)c(NC(=N)Nc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (0.58 g, 0.0027 mol), N-[3-(2-chloro-6-fluorobenzyloxy)-6-methylpyrid-2-yl]-N'-4-chlorophenylthiourea (1.00 g, 0.0023 mol) and methanolic ammonia solution (30 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by recrystallisation from ethanol gave the desired product. Yield 0.52 g (54%), m.p. 148°-149 ° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23].[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Reactant: COCCN
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNCCOC)C1C

Procedure:
The procedure of Example 13 is repeated, starting with 3.21 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester and 890 mg. of methoxyethylamine in 30 ml., to give 1.5 g. of the crude product as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[N:6][CH:7]=1.[Li]CCCC.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:31])=[C:27]([CH:30]=1)[CH:28]=[O:29]>C1COCC1.CCCCCC>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:31])=[C:27]([CH:28]([C:2]2[CH:7]=[N:6][C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[CH:4][CH:3]=2)[OH:29])[CH:30]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: Fc1ccc(Nc2ccc(Br)cn2)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(Nc2ccc(F)cc2F)nc1)c1cc(Br)ccc1Cl
Reaction time: 0.33 h

Procedure:
(5-Bromo-pyridin-2-yl)-(2,4-difluoro-phenyl)-amine (3 g; 10.5 mmol) is dissolved in THF (70 ml) and cooled to −78 C. nBuLi (14.5 ml of a 1.5M solution in hexane; 23 mmol) is added dropwise and the resulting yellow suspension stirred or 20 min. 5-Bromo-2-chlorobenzaldehyde in THF (6 ml) is added at −78 C. After 5 min at −78 C, the reaction mixture is warmed to −50 C, poured on water and extracted with TBME twice. The combined organic phases are dried over Na2SO4 and evaporated to dryness. Purification via chromatography (SiO2; acetone/hexanes 6/94>12/88) yields the title compound as orange viscuous oil, (2.58 g; 58%) which is used in the next step. b) (5-Bromo-2-chloro-phenyl)-[6-(2,4-difluoro-phenylamino)-pyridin-3-yl]-methanone
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:32])=[N:8][C:9]([CH3:31])=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)=[O:5])C.Cl>[OH-].[Na+]>[C:4]([C:6]1[C:7]([CH3:32])=[N:8][C:9]([CH3:31])=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:18][CH:19]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)cc(C)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(C(=O)O)c(C)n1
Reaction time: 24 h
Yield: 60 %

Procedure:
150 mg of the compound obtained in Example 40 was dissolved in 2 ml of 1N NaOH. The solution was stirred at 60°-70° C. for 24 hours, and then cooled. The pH of the reaction mixture was adjusted to 3 with 1N HCl. The precipitate obtained was collected by filtration, washed with water, and then dried to give 84 mg of a colorless powder of the title compound (yield: 60%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[C:11](=O)[CH2:10][CH2:9][CH2:8]3.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[C:11](=[N:16][OH:17])[CH2:10][CH2:9][CH2:8]3
Reactant: NO
Reactant: O=C1CCCc2cc3c(cc21)OCC3
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCCc2cc3c(cc21)OCC3

Procedure:
A mixture containing 46 g of the compound of Example 1, 60 g of hydroxylamine hydrochloride and 60 g of anhydrous sodium acetate in 410 ml of ethanol is brought to reflux for 5 hours. The mixture is then cooled and diluted with water, extracted with methylene chloride, dried and evaporated to dryness. The dry residue is recrystallized in ethanol.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([C:16]#[C:17][Si](C)(C)C)[CH:15]=1)[O:12][C:11]([CH3:23])([CH3:22])[CH2:10][C:9]2([CH3:25])[CH3:24])=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:16]([C:14]1[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:23])([CH3:22])[CH2:10][C:9]2([CH3:24])[CH3:25])#[CH:17]
Reactant: CCOC(=O)c1cc(C#C[Si](C)(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#Cc1cc(C(=O)O)cc2c1OC(C)(C)CC2(C)C
Yield: 83.2 %

Procedure:
A solution of ethyl-8-trimethylsilanylethynyl-2,2,4,4-tetramethylchroman-6-carboxylate (Intermediate 209, 0.525 g, 1.47 mmol) in ethanol (5 mL) was treated with 2N aqueous sodium hydroxide solution (5 mL, 10 mmol) and the resulting solution was adjusted to pH ˜15 with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a brown solid (0.316 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][C:21]1[C:25]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[C:24]([CH3:35])[NH:23][N:22]=1>>[CH3:35][C:24]1[C:25]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH:19][C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:17][CH2:16][CH2:15][CH:14]5[CH3:18])[CH2:9]4)=[CH:7][C:2]=3[CH3:1])=[O:31])=[CH:28][CH:27]=2)=[C:21]([CH3:20])[NH:22][N:23]=1
Reactant: Cc1n[nH]c(C)c1-c1ccc(C(=O)O)cc1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-c2c(C)n[nH]c2C)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(3,5-dimethyl-1H-pyrazol-4-yl)benzoic acid. MS: 458.3 (M+H).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:10]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][CH:7](O)[C@@H:6]1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:2]=[CH2:3].CN(C)C=O.C(Cl)(=O)C([Cl:45])=O>ClCCl>[CH2:1]([O:4][C@H:5]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:10]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][CH:7]([Cl:45])[C@@H:6]1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1[C@@H](OCc2ccccc2)[C@@H](COCc2ccccc2)OC(O)[C@@H]1OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCO[C@H]1[C@@H](OCc2ccccc2)[C@@H](COCc2ccccc2)OC(Cl)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
Compound Y (505 mg, 1.03 mmol) in dry dichloromethane (8 ml) was treated with N,N-dimethylformamide (0.55 ml) and oxalyl chloride (0.55 ml) at room temperature for 45 minutes. The mixture was diluted with ice-cold toluene (40 ml), then quickly washed with ice-cold water (6 ml) and ice-cold, saturated, aqueous sodium hydrogencarbonate (6 ml), dried (Na2SO4) and concentrated to give crude Z in quantitative yield.
Reaction SMILES: [C:1]1([CH:7]([Ge:12](Cl)(Cl)Cl)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S>CC(C)=O>[C:1]1([CH:7]([GeH3:12])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(c1ccccc1)[Ge](Cl)(Cl)Cl
Agent: S
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(O)CC([GeH3])c1ccccc1

Procedure:
16.4 g (0.05 mol) of 3-phenyl-3-(trichlorogermyl)propionic acid was dissolved in 200 ml of anhydrous acetone. 12.6 g (0.16 mol) of anhydrous pyridine was added to the solution under cooling with an ice bath, followed by stirring. Dry hydrogen sulfide was introduced into the mixture for one hour. The acetone was removed and the residue was dissolved in 50 ml of ethanol. The solution was added to 400 ml of water to precipitate the crystal. The crystal was recrystallized from a mixture of methyl acetate and benzene (1:3) to obtain 12.7 g of crystalline sesquisulfide of 3-phenyl-3-germylpropionic acid. ##STR14## sesquisulfide of 3-phenyl-3-germylpropionic acid (18).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2([NH2:16])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2([NH:16][C:25](=[O:26])[CH2:24][Cl:23])[CH2:13][O:12][C:11]([CH3:14])([CH3:15])[O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)CCl
Reactant: CC1(C)OCC(N)(c2ccnc(Br)c2)CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OCC(NC(=O)CCl)(c2ccnc(Br)c2)CO1
Reaction time: 0.08 h

Procedure:
To a solution of 5-(2-bromo-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxan-5-ylamine (9.5 g, 33.1 mmol) in DCM (100 ml) was added aq. Na2CO3 (8.7 g in 50 ml) at 0° C. and stirring continued for 5 min. Chloroacetyl chloride (2.9 ml, 36.41 mmol) was added to the resultant reaction mixture drop wise and stirred for 30 min at 0° C. Reaction mass was diluted with DCM (200 ml) and organic layer was washed successively washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain brown solid. The product was directly used in the next step with further purification. Yield=10.2 g (85%). TLC (50% ethyl acetate in hexane) Rf=0.15; LCMS: RtH8=0.55 [M+1]+=363.0 and 364.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.N1C=CC=CC=1.[Cl:15][C:16]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29]C)=[CH:20][CH:19]=[CH:18][N:17]=1>O>[ClH:15].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1[C:16]2[O:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1Oc1cccnc1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: c1ccc2c(c1)Oc1cccnc1O2
Temperature: 100 °C

Procedure:
Anhydrous pyridine hydrochloride is prepared by distillation to a temperature of 220° C. from a mixture of 42 g of pyridine and 50 ml of concentrated hydrochloric acid. Under a nitrogen atmosphere, the pyridine hydrochloride is allowed to cool to 100° C. and 5 g of 2-chloro-3-(2-methoxyphenoxy)pyridine is added and the mixture is refluxed 1 hour. The mixture is cooled and 200 ml of water is added. The mixture is extracted with 250 ml diethyl ether and the extracts are washed with 10 ml of concentrated ammonium hydroxide. The ether layer is dried and evaporated to yield the pyrido[2,3-B][1,4]benzodioxin, mp 95°-97° C., after sublimation at 0.1 mm pressure.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:15])[O:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11])[CH2:2]1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[CH:27][NH:26][N:25]=2)[CH:20]=[C:19]([CH3:29])[N:18]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:12][C:10]([F:13])([F:11])[C@@H:9]([O:8][C:7](=[O:15])[NH:6][C@H:3]1[CH2:4][CH2:5][N:1]([C:17]2[N:18]=[C:19]([CH3:29])[CH:20]=[C:21]([NH:23][C:24]3[CH:28]=[CH:27][NH:26][N:25]=3)[N:22]=2)[CH2:2]1)[CH3:14]
Reactant: C[C@H](OC(=O)N[C@H]1CCNC1)C(F)(F)F
Reactant: Cc1cc(Nc2cc[nH]n2)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc[nH]n2)nc(N2CC[C@H](NC(=O)O[C@@H](C)C(F)(F)F)C2)n1
Temperature: 110 °C
Reaction time: 15 h

Procedure:
To a solution of (2S)-1,1,1-trifluoropropan-2-yl (3S)-pyrrolidin-3-ylcarbamate (50 mg) in DMSO (5 ml) was added 2-chloro-6-methyl-N-(1H-pyrazol-3-yl)pyrimidin-4-amine (46 mg) prepared in Referential Example 1 and DIEA (28 mg) at room temperature. The resulting mixture was stirred at 110° C. for 15 hours and then cooled to room temperature. The mixture was purified with preparative RP-HPLC to give (2S)-1,1,1-trifluoropropan-2-yl{(3S)-1-[4-methyl-6-(1H-pyrazol-3-ylamino)pyrimidin-2-yl]pyrrolidin-3-yl}carbamate as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:14])[CH:3]=1.[CH3:15][C:16]1[C:20](B(O)O)=[C:19]([CH3:24])[O:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O>[Cl:14][C:4]1[CH:3]=[C:2]([C:20]2[C:16]([CH3:15])=[N:17][O:18][C:19]=2[CH3:24])[CH:13]=[CH:12][C:5]=1[NH:6][CH2:7][C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)CNc1ccc(Br)cc1Cl
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1ccc(NCC(F)(F)F)c(Cl)c1
Temperature: 90 °C

Procedure:
A mixture of 4-Bromo-2-chloro-N-(2,2,2-trifluoroethyl)aniline (5280 mg, 18.3 mmol), 3,5-dimethylisoxazole-4-boronic acid, pinacol ester (4082.76 mg, 18.3 mmol), PEPPSI″-IPr catalyst (1247.24 mg, 1.83 mmol), Cesium carbonate (17889.52 mg, 54.91 mmol) in 120 mL DME:H2O (2:1) was heated to 90° C. under argon. The reaction mixture was then cooled and partitioned between water and ethyl acetate. The organic layer was washed with water then brine and dried over sodium sulfate. Purification on silica gel (Hexanes/EtOAc) afforded 2-chloro-4-(3,5-dimethylisoxazol-4-yl)-N-(2,2,2-trifluoroethyl)aniline.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][N:14]([CH3:18])[CH2:15]3)[CH2:11]2)[CH:7]=[CH:6][C:5]=1[N+:19]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:19][C:5]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:11][CH:12]3[CH:16]([CH2:15][N:14]([CH3:18])[CH2:13]3)[CH2:17]2)=[CH:9][C:4]=1[C:3]([NH:2][CH3:1])=[O:22]
Reactant: [H][H]
Reactant: CNC(=O)c1cc(N2CC3CN(C)CC3C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)c1cc(N2CC3CN(C)CC3C2)ccc1N
Yield: 101.7 %

Procedure:
N-methyl-5-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-nitrobenzamide (Intermediate 13A) (900 mg, 2.96 mmol) was dissolved in ethanol (140 mL). The resulting solution was hydrogenated using the H-cube at 40° C. under 30 bar pressure of hydrogen, with a flow rate of 1 mL per minute through a 10% palladium on charcoal cartridge. The reaction mixture was concentrated to afford 2-amino-N-methyl-5-(5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)benzamide, (824 mg, 3.01 mmol).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1.[C:22]1([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ICC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Product: CCOC(=O)COc1cccc2c1CCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 68 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and 2,2-diphenylethyl iodide, the procedure of Example 48 was otherwise repeated to synthesize the title compound. Yield 68%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:15][Mg]Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:14])[CH3:15])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: C[Mg]Cl
Reactant: O=Cc1cnc(-c2ccc(Cl)cc2)s1
Solvent: C1CCOC1
Product: CC(O)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of 2-(4-Chloro-phenyl)-thiazole-5-carbaldehyde (4.95 g, 22.14 mmol) in THF (65 ml) at 0° C. under an atmosphere of nitrogen was added methyl magnesium chloride (3M in THF; 8.11 ml, 24.35 mmol) dropwise over a period of 5 minutes. The reaction was then allowed to warm to room temperature and stirred for a further 2 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (100 ml) and stirred for 5 minutes, before the methanol is removed under reduced pressure. The resulting heterogeneous mixture was then extracted with ethyl acetate (2×100 ml), the combined organics dried over magnesium sulphate and the solvent removed under reduced pressure to give 1-[2-(4-Chloro-phenyl)-thiazol-5-yl]-ethanol (4.71 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12](O)=[O:13]>[OH-].[Na+].O>[Cl:8][C:7]1[C:2]2[NH:1][C:12](=[O:13])[CH2:11][S:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CBr
Reactant: Nc1c(S)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CSc2cccc(Cl)c2N1
Yield: 95.3 %

Procedure:
2-Amino-3-chlorothiophenol (2.5 g) was dissolved in a solution of sodium hydroxide (690 mg) in water (40 ml), and bromoacetic acid (2.4 g) was added thereto with stirring. After stirring at 70° C. for 3 hours, the precipitated crystals were filtered, washed with water and dried to obtain 2.98 g of the objective 5-chloro-2,3-dihydro-1,4-benzothiazine-3-one (m.p. 160°-161° C.).
Reaction SMILES: C(OC(=[N:6][O:7][CH2:8][CH2:9][N:10]([CH3:30])[CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[C:18]2[CH3:27])[C@H:14]([OH:28])[C@@H:13]1[OH:29])C)C.C([O-])(O)=O.[Na+].[OH:36][S:37]([OH:40])(=[O:39])=[O:38]>>[S:37]([OH:40])([OH:39])(=[O:38])=[O:36].[NH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:30])[CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[C:18]2[CH3:27])[C@H:14]([OH:28])[C@@H:13]1[OH:29]
Reactant: CCOC(C)=NOCCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CN(C)CCON)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Compound 6a (50 mg, 0.11 mmol) was dissolved in 2 mL of 2N H2SO4 and stirred for 2 days at room temperature. The reaction mixture was neutralized with NaHCO3 and lyophilized. The compound was extracted with EtOH (2×10 mL) and concentrated to dryness. The residue was purified by column chromatography (silica gel 230-400 mesh, elution with 7:1:0.3 chloroform:methanol:NH4OH). The desired fractions were combined, concentrated, and dried in vacuo. The product was dissolved in 3 mL of EtOH and 2N H2SO4 was added dropwise. The resulting sulfate salt that precipitated out was filtered, and washed with EtOH. This product, which was hygroscopic in nature, was dissolved in water (2 mL) and lyophilized to give a white solid: yield 20 mg (29%), MS: m/z 354 (M+H)+; 1HNMR (DMSO-d6) δ 8.25 (s, 1H, H-2), 7.80 (bs, 2H, O—NH2), 5.87 (d, 1H, H-1′, J1′,2′=5.7 Hz), 4.88 (t, 1H, H-2′, J2′,3′=5.2 Hz), 4.35-4.40 (bm, 1H, H-4′), 4.23 (t, 1H, H-3′, J2′,3′=3.2 Hz), 4.10 (t, 2H, NH2O—CH2), 3.50-3.57 (m, 1H, 5′-CH2), 3.65-3.72 (m, 1H, 5′-CH2), 3.45 (bm, 2H, N(CH3)—CH2), 2.85 (s, 3H, N—CH3), 2.58 (s, 3H, 8-CH3); UV λmax, nm, pH 1, 274 (∈ 15,200), pH 7, 276 (∈ 15,500), pH 13, 277 (∈ 15,900). Anal. (C14H23N7O4.2.2H2SO4.0.1C2H5OH.0.5H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:38])/[CH:24]=[CH:25]/[C@@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5C(OC(C)(C)C)=O)[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>CC(O)C.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:38])/[CH:24]=[CH:25]/[C@@H:26]5[CH2:30][CH2:29][CH2:28][NH:27]5)[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: O=C(/C=C/[C@@H]1CCCN1)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
tert-Butyl (2S)-2-[(1E)-3-{4-[(3-chloro-4-fluorophenyl)amino]-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-7(6H)-yl}-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate from Example 14A (397 mg, 0.712 mmol) was dissolved in 2-propanol (4 mL), and a 4 M solution of gaseous hydrogen chloride in dioxane (0.36 mL) was added. The mixture was stirred for 3 h at 70° C. The solvent was then removed in vacuo. The residue was dissolved in ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The crude product was purified by preparative HPLC to yield 139 mg (42%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:13]([O-])=O)[C:3]=1[OH:16].Cl.CO>CC(O)=O.[Pd]>[Cl:1][C:2]1[C:3]([OH:16])=[C:4]([NH2:13])[C:5](=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:6]([OH:8])=[O:7]
Reactant: Cc1c(Cl)c(O)c([N+](=O)[O-])c(C(=O)O)c1Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(Cl)c(O)c(N)c(C(=O)O)c1Cl
Yield: 89.6 %

Procedure:
4,6-Dichloro-3-hydroxy-5-methyl -2nitrobenzoic acid (69 mg, 0.26 mmol) was dissolved in HOAc (10 mL), 10% Pd/C (10 mg) and concentrated HCl (33μ, 0.39 mmol) were added. Hydrogenation at room temperature and at atmospheric pressure for 2 h gave a slurry to which methanol (5 mL) was added and the catalyst was filtered off. Evaporation of the solvent, co-evaporation with toluene (10 mL) followed by vacuum-drying over KOH gave 63 mg of a crude product. Purification by flash column chromatography (SiO2), EtOAc-HOAc 45:1) yielded 55 mg of the title compound. Mp: 192° C. (dec); 1H NMR (DMSO-d6): δ 2.27 (s, 3H); 13C NMR (DMSO-d6): δ 167.43, 139.25, 136.01, 122.90, 121.26, 120.37, 116.89, 16.96;MS (EI, 70 eV): m/z (rel.int.) 237/235 (M+, 45/79), 219/217 (37/64), 191/189 (60/100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1.[NH2:30][CH2:31][C@@H:32]([OH:35])[CH2:33][OH:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:30][CH2:31][C@@H:32]([OH:35])[CH2:33][OH:34])=[O:25])=[CH:27][CH:28]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)cc2)c2ccc(Cl)cc2F)ccc1=O
Reactant: NC[C@@H](O)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NC[C@@H](O)CO)cc2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-[1-(4-chloro-2-fluoro-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-benzoic acid (example 311, step 4) was coupled with (R)-3-amino-1,2-propanediol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a colourless foam, MS (ESI+): m/z=487.3 [M+H]+.