Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11]/[C:12](/[CH3:18])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15].[CH3:19][C:20]1[N:21]([CH2:27][CH2:28][O:29][CH2:30][C:31](=O)[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:22]([CH3:26])=[C:23]([CH3:25])[N:24]=1>CO>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:31]([CH2:30][O:29][CH2:28][CH2:27][N:21]2[C:22]([CH3:26])=[C:23]([CH3:25])[N:24]=[C:20]2[CH3:19])=[C:32]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)CC(=O)COCCn1c(C)nc(C)c1C
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: CO
Product: CCOC(=O)C1=C(COCCn2c(C)nc(C)c2C)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 46.7 %

Procedure:
A solution of 2,3-dichlorobenzaldehyde (8.75 g), methyl 3-aminocrotonate (5.75 g) and ethyl 4-[2-(2,4,5-trimethyl-1-imidazolyl)ethoxy]acetoacetate (14.1 g) in 50 ml of methanol was stirred at reflux temperature for 5 hours. After evaporation to dryness, the residue was dissolved in 2N hydrochloric acid (200 ml) and washed with diethyl ether (3×100 ml) followed by extraction with methylene chloride (4×150 ml). The combined methylene chloride extracts were washed with saturated aqueous sodium carbonate solution (2×200 ml), dried (Na2CO3), filtered and evaporated to give a beige solid (12.5 g). The crude product was chromatographed on silica (40 g), eluting with ethyl acetate. The appropriate fractions were combined and evaporated and the resultant oil (2.1 g) crystallised from diethyl ether (10 ml) to give the title compound, (1.5 g), m.p. 123°-125° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.[CH:23]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[O:28][C:27]=2[C:26](B(O)O)=[CH:25][CH:24]=1>>[CH:23]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[O:28][C:27]=2[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:20]([CH3:21])[CH3:22])[CH:5]=[C:6]3[C:10]=2[NH:9][C:8]2[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]3=2)[CH:24]=1
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Reactant: OB(O)c1cccc2c1oc1ccccc12
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccc4c(c3)oc3ccccc34)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 4-dibenzofuranboronic acid in step 1.F.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[C:9]([O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:5]2[N:4]=1.CO.[Br:23]N1C(=O)CCC1=O>C1COCC1>[Br:23][C:11]1[N:5]2[C:6]([CH:7]=[N:8][C:3]([S:2][CH3:1])=[N:4]2)=[C:9]([O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[CH:10]=1
Reactant: CSc1ncc2c(OCOCC[Si](C)(C)C)ccn2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ncc2c(OCOCC[Si](C)(C)C)cc(Br)n2n1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
Into a 1-Neck round-bottom flask, 2-Methylsulfanyl-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazine (1.05 g, 3.37 mmol), Tetrahydrofuran (50 mL) and Methanol (25 mL) were added and stirred at room temperature. N-Bromosuccinimide (0.630 g, 3.54 mmol) in THF (20 mL) was added to the reaction mixture . The reaction was stirred at room temperature for 2 hours. LCMS suggested no SM. The solvent was removed under vacuum. The reaction was partitioned with water and Et2O. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as eluant (5 to 20% EtOAc). The collected fractions afforded 7-Bromo-2-methylsulfanyl-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazine as an oil (1.10 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[N:7]=[C:6]1[CH2:13]O.C(N(CC)CC)C.S(Cl)([Cl:29])=O>ClCCl>[Cl:29][CH2:13][C:6]1[N:5]([CH2:4][C:3]2[C:2]([Cl:1])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cn(Cc2c(Cl)cccc2Cl)c(CO)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cn(Cc2c(Cl)cccc2Cl)c(CCl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
210 mg (0.70 mmol) of the compound from Example 37A were dissolved in 10 ml of dichloromethane, and 145 μl (1.04 mmol) of triethylamine and 61 μl (0.83 mmol) of thionyl chloride were added at 0° C. The mixture was stirred at RT for 24 h. A further 200 μl (2.72 mmol) of thionyl chloride were then added, and the mixture was stirred under reflux for 15 min. Under reduced pressure, the reaction mixture was then freed from all volatile components. This gave, in a purity of 88%, 200 mg (80% of theory) of the target compound, which was reacted further without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O=S(Cl)Cl.C(Cl)Cl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccccc1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(Cc1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(4-fluorophenyl)acetic acid (5.0 g, 32.5 mmol, 1.00 equiv) in SOCl2 (30 mL) was heated for 3 hr at reflux in a 50-mL round-bottom flask. Most of SOCl2 was removed under vacuum, and the residue was added dropwise into a solution of AlCl3 (12.8 g, 96.2 mmol, 3.00 equiv) and fluorobenzene (6.1 g, 63.54 mmol, 2.00 equiv) in DCM (20 mL) at 0° C. The resulting solution was allowed to react, with stirring, for 2 hrs at room temperature.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[H-].[Na+].Br[CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([O:12][CH2:11][CH2:10][O:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC1CCOC1
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCCOC2CCOC2)cc1
Reaction time: 0.17 h

Procedure:
Tetrahydrofuran-3-ol (0.881 g) in tetrahydrofuran (15 mL) was treated with 60% sodium hydride (0.8 g). After 10 minutes, ((2-bromoethoxy)methyl)benzene (3.23 g) was added. The solution was stirred for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was separated, and was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 1:1 ethyl acetate:hexane to provide the title compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][CH2:11][NH2:12].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O>O.C(O)C>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][CH2:11][NH:12][CH:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[Cl:13])[C:1]#[N:2]
Reactant: NCCc1cccs1
Reactant: [C-]#N
Reactant: O=Cc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC(NCCc1cccs1)c1ccccc1Cl
Temperature: 45 °C
Reaction time: 2 h

Procedure:
9,8 g (0,2 mol) of sodium cyanide is dissolved in 70 ml of water and to the solution first 32,8 g (0,2 mol) of 2-(2-thienyl)ethylamine hydrochloride, then in a period of a few minutes, the solution of 28,2 g (0,2 mol) of o-chlorobenzaldehyde in 30 ml of ethanol are added. During the addition the temperature of the mixture raises to 45° C. The reaction mixture is then stirred at 60° C. for 2 hours, then cooled to room temperature and diluted with 50 ml of water. The resulting oily product is extracted with 100 ml of 1,2-dichloroethane, the organic phase is washed to cyanide-free with 2×50 ml of water, the traces of 2-(2-thienyl)ethylamine are removed by treatment with 20 ml of 3% hydrochloric acid solution. The residual fast crystallizing oil is the product. Weight: 52 g (94%) mp.: 40-41° C. The product was identified as written in Example 1. Quality of the product is identical to that of the product prepared according to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH:8]=O)=[O:5].Cl.[NH2:16][OH:17].[C:18]([O-:21])(=O)C.[Na+]>CO>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:16]([CH:18]=[O:21])[OH:17])=[O:5]
Reactant: NO
Reactant: O=CCNC(=O)c1cc(Cl)ccc1Cl
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=CN(O)CCNC(=O)c1cc(Cl)ccc1Cl
Reaction time: 18 h
Yield: 166.7 %

Procedure:
To a solution of 2,5-dichloro-N-(2-oxo-ethyl)-benzamide (0.67 g, 2.9 mmol) in MeOH (100 mL) was added hydroxylamine hydrochloride (0.41 g, 5.8 mmol) and sodium acetate (0.48 g, 5.8 mmol). The mixture was stirred 18 h and the MeOH was removed in vacuo. The residue was dried in vacuo for 18 h and used without further purification to provide the title compound (1.34 g) as a white solid. ESMS: M+H=247.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:29][C:26]1[CH:25]=[CH:24][C:23]([C@H:22]2[C:15]3=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]3[CH2:19][CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4ccc(F)c(Cl)c4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
A mixture of (3-chloro-4-fluorophenyl)boronic acid (933 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL), cesium carbonate (581 mg), diacetoxycopper (648 mg) and powdered 4A MS (4 g) in MeCN (18 mL) was stirred at room temperature for 3 days. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc-THF/IPE to give (9S)-9-[4-(3-chloro-4-fluorophenoxy)phenyl]-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (290.6 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].N1C=CC=CC=1.[OH:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>CN(C1C=CN=CC=1)C.CC#N.C(Cl)Cl>[OH:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[S:3][C:4]([S:10]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])=[O:29]
Reactant: O=C(Cl)c1ccccc1O
Reactant: NC(=O)c1cc(S(=O)(=O)N2CCOCC2)sc1N
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1cc(S(=O)(=O)N2CCOCC2)sc1NC(=O)c1ccccc1O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Amino-5-(morpholine-4-sulfonyl)-thiophene-3-carboxylic acid amide (150 mg, 0.51 mmol) is mixed with pyridine (63 μL, 0.77 mmol) and DMAP (15 mg, 0.12 mmol) in MeCN (1 mL). 2-Hydroxy-benzoyl chloride (103 mg, 0.65 mmol) is dissolved in 2 mL of MeCN and added to the reaction mixture. The resulting solution is stirred at 60° C. for 2 h, then diluted with DCM and finally washed with aqueous NaHCO3. The organic phase is evaporated to yield a residue which is purified by preparative chromatography to afford the desired product.
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10].[CH3:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C@@H:27]1[CH2:44][C:43]2[CH:42]=[C:41]([OH:45])[CH:40]=[CH:39][C:38]=2[C@@H:37]2[C@@H:28]1[C@H:29]1[C@@:33]([CH2:35][CH2:36]2)([CH3:34])[C@@H:32]([OH:46])[CH2:31][CH2:30]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:45][C:41]1[CH:40]=[CH:39][C:38]2[C@@H:37]3[C@H:28]([C@H:29]4[C@@:33]([CH2:35][CH2:36]3)([CH3:34])[C@@H:32]([OH:46])[CH2:31][CH2:30]4)[C@H:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:16])[C:9](=[O:10])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:44][C:43]=2[CH:42]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CNCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)COC(=O)N(C)CCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reaction time: 2.5 h

Procedure:
N-Methylmorpholine (0.028 ml.) and isobutyl chloroformate (0.038 ml.) were successively added to a stirred solution of 7α-(9-methylaminononyl)oestra-1,3,5(10)-trien-3,17β-diol (Example 28; 0.08 g.) in tetrahydrofuran (3 ml.) and the mixture was stirred at laboratory temperature for 150 minutes. Saturated aqueous sodium bicarbonate solution (2 ml.) was added and the mixture was extracted three times with methylene chloride (10 ml. each time). The combined extracts were washed with water (5 ml.), dried and evaporated to dryness and there was thus obtained as residual oil isobutyl N-[9-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)nonyl]-N-methylcarbamoate.
Reaction SMILES: [CH2:1]([N:7]1[C:12](=O)[CH:11]2[CH:9]([C:10]2([CH:23]([CH3:25])[CH3:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O1CCCC1.B.CO>O1CCCC1>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH:23]([CH3:24])[CH3:25])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C2C(C1=O)C2(c1cccc([N+](=O)[O-])c1)C(C)C
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1)C2(c1cccc([N+](=O)[O-])c1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-hexyl-6-isopropyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (Preparation 59, 0.57 g, 1.6 mmol) in tetrahydrofuran (6 ml), under nitrogen, was added borane tetrahydrofuran complex (1M in tetrahydrofuran, 3.0 ml, 3.0 mmol) and the reaction mixture was heated under reflux for 2 h. The reaction mixture was cooled to room temperature before the addition of further borane tetrahydrofuran complex (1M in tetrahydrofuiran, 3.0 ml, 3.0 mmol). After 20 min, the reaction mixture was cooled to room temperature and methanol (8 ml) was added and then the reaction mixture was once more heated under reflux for 6 h. The reaction mixture was concentrated in vacuo and the residue was dried under vacuum at room temperature. The residue was treated with dichloromethane (4 ml), filtered and purified by chromatography on a Biotage Flash40S™ cartridge packed with silica gel (40 g) eluting with hexane:ethyl acetate (6:1). The title compound was obtained initially as a yellow oil which crystallised upon standing (0.2 g, 40%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([S:25]([O-:28])(=O)=[O:26])[CH:8]=[CH:9][C:10]=1[N:11]=[N:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[CH:15][C:14]=1[NH:21][C:22](=[O:24])[CH3:23])(=[O:4])=[O:3].[Ca+2].CS(C1C=C(S([O-])(=O)=O)C=CC=1N=NC1C=C([Cl:48])C(O)=CC=1NC(=O)C)(=O)=O.CC(N(C)C)=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:22]([NH:21][C:14]1[C:13]([N:12]=[N:11][C:10]2[CH:9]=[CH:8][C:7]([S:25]([Cl:48])(=[O:28])=[O:26])=[CH:6][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:18][C:17]([Cl:19])=[C:16]([OH:20])[CH:15]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1cc(O)c(Cl)cc1N=Nc1ccc(S(=O)(=O)[O-])cc1S(C)(=O)=O
Agent: [Ca+2]
Solvent: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=O)Nc1cc(O)c(Cl)cc1N=Nc1ccc(S(=O)(=O)Cl)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 18 g of calcium 3-methylsulfonyl-4-(2-acetylamino-5-chloro-4-hydroxyphenylazo)phenylsulfonate, 25 ml of dimethylacetamide, and 54 ml of acetonitrile was added dropwise to 18 ml of phosphorus oxychloride at room temperature with stirring. After completion of the addition, the reaction was allowed to proceed at 60° C. for 3 hours, and the reaction mixture was cooled to room temperature and then poured in 1 l of ice water. The mixture was stirred at a temperature of 10° C. or less for 1 hour and the resulting crystalline precipitate was collected by filtration, washed with water and air-dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:27])=[C:5]([C:18]([O:25][CH3:26])=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:27])=[C:5]([C:18]([O:25][CH3:26])=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OCC(=O)OC(C)(C)C
Yield: 52.6 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-hydroxybenzoate (1.09 g, 2.53 mmol) was dissolved in acetone (50 ml) and after adding thereto anhydrous sodium carbonate (0.420 g, 3.03 mmol) and tert-butyl bromoacetate (0.592 g, 3.03 mmol), the solution was refluxed under heating for 3 hours. The reaction solution was filtered, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (0.650 g, 1.33 mmol, 53%).
Reaction SMILES: C([O:5][NH:6][C:7]([C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[C:13]([F:24])[C:12](=[O:25])[N:11]([CH3:26])[CH:10]=1)=[O:8])(C)(C)C.C(O)(C(F)(F)F)=O>>[OH:5][NH:6][C:7]([C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[C:13]([F:24])[C:12](=[O:25])[N:11]([CH3:26])[CH:10]=1)=[O:8]
Reactant: Cn1cc(C(=O)NOC(C)(C)C)c(Nc2ccc(Br)cc2F)c(F)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C(=O)NO)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reaction time: 96 h
Yield: 33 %

Procedure:
4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydroxyamide was prepared from 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid tert-butoxy-amide by TFA mediated deprotection. 4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid tert-butoxy-amide (35 mg, 0.081 mmol) was treated with TFA (0.63 mL). After 4 days stirring, the reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography (10% MeOH in methylene chloride) followed by saturated NaHCO3 solution wash of an ethyl acetate solution of the product gave clean desired product (10 mg, 33%); MS APCI (+) m/z 356, 358 (M—OH, Br pattern) detected; 1H NMR (400 mHz, CD3OD) δ 7.84 (s, 1H), 7.35 (dd, 1H), 7.28 (d, 1H), 7.01 (td, 1H), 3.57 (s, 3H).
Reaction SMILES: ClCC[CH2:4][CH2:5][C:6](Cl)=[O:7].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-:16].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[Cl:16][CH2:4][CH2:5][C:6]([C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)=[O:7]
Reactant: [Cl-]
Reactant: O=C(Cl)CCCCCl
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(CCCl)c1ccc(F)cc1
Yield: 26.4 %

Procedure:
2-chloroethylpropionyl chloride (0.63 g), fluorobenzene (0.48 g), and aluminium chloride (0.8 g) were reacted in nitrobenzene (2.3 mL) at 0° C., followed by treatment with hydrochloric acid to obtain the title compound (0.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33](=[O:37])[CH2:34][C:35]#[N:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12.[CH:38]1([CH:41]=O)[CH2:40][CH2:39]1.N1CCCCC1>CCO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([C:34](=[CH:41][CH:38]3[CH2:40][CH2:39]3)[C:35]#[N:36])=[O:37])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reactant: O=CC1CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reaction time: 0.33 h
Yield: 26.8 %

Procedure:
A solution of 3-((S)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (304.2 mg, 0.60 mmol, 1.00 equiv), cyclopropanecarbaldehyde (210 mg, 3 mmol, 5 equiv), piperidine (102 mg, 1.20 mmol, 2 equiv) in EtOH (20 mL) was stirred overnight at rt. The resulting mixture was concentrated under vacuum. Then concentrated and purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 90 mg (22.3%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 560 (M-TFA+1)H-NMR (400MHz, CDCl3, ppm): 11.94 (brs, 1H), 8.27 (s, 1H), 7.62-7.58 (m, 1H), 7.19-7.13 (m, 2H), 7.04-6.98 (m, 2H), 6.91 (d, J=11.2 Hz, 1H), 6.81 (d, J=11.2 Hz, 1H), 6.01 (brs, 1H), 4.96-4.86 (m, 1H), 4.76-4.62 (m, 2H), 3.71-3.62 (m, 1H), 3.61-3.45 (m, 1H), 2.12-1.82 (m, 5H), 1.30-1.28 (m, 2H), 0.94-0.89 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20][CH:21]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncccc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ncccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 14 h
Yield: 64.2 %

Procedure:
3-Bromopyridine-2-carboxylic acid methyl ester (4.0 g, 18.6 mmol, 1.0 eq.) was combined with a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (5.8 g, 18.6 mmol, 1.0 eq.) in THF (100 mL), under nitrogen. A solution of Na2CO3 (7.9 g, 74.5 mmol, 4.0 eq.) in water (37 mL) was added, followed by the addition of PdCl2(PPh3)2 (650 mg, 930 μmol, 0.05 eq.). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The resulting solution was diluted with EtOAc (100 mL), then washed with saturated aqueous NaCl (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:20) to yield 3′,6′-dihydro-2′H-[3,4]bipyridinyl-2,1′-dicarboxylic acid 1′-t-butyl ester 2-methyl ester (3.8 g) as colorless oil.