Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:25]=[N:26][N:27]([CH2:29][C:30]5[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=5)[N:28]=4)[CH:19]=3)[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])C.[CH2:38]([CH2:40][NH2:41])[OH:39]>CS(C)=O>[OH:39][CH2:38][CH2:40][NH:41][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:25]=[N:26][N:27]([CH2:29][C:30]5[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=5)[N:28]=4)[CH:19]=3)[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cccc(-c4nnn(Cc5ccc(OC)cc5)n4)c3)csc12
Solvent: CS(C)=O
Product: COc1ccc(Cn2nnc(-c3cccc(OCc4csc5c(C(=O)NCCO)cnc(N)c45)c3)n2)cc1
Temperature: 160 °C

Procedure:
A solution of 4-amino-3-{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.050 g, 0.10 mmol) (from Example 28 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160° C. for 2 hours in a microwave reactor. The precipitate was filtered and dried to give 4-amino-3-{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide. (Yield 18.0 mg, 35%).
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>>[F:1][CH2:2][C:3]([N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: Brc1ccccn1
Reactant: O=C(CF)Nc1ccccc1
Product: O=C(CF)N(c1ccccc1)c1ccccn1
Yield: 75.2 %

Procedure:
Using 2-fluoroacetanilide (4.6 g) and 2-bromopyridine (9.5 g), a reaction was made in the same manner as in 1) of Production Example 14. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:1.5) produced 2-fluoro-N-(2-pyridyl)acetanilide (5.2 g, crude product) as a red oil.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([F:14])[CH:8]=1.CN(C)[CH:17]=[O:18].S(=O)(=O)(O)[O-].[K+]>C1(C)C=CC=CC=1.O1CCCC1>[F:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[CH3:13])[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Cc1ccc(Br)cc1F
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
tert-Butyllithium (31 ml of a 1.7 M solution in toluene, 52 mmol) was added slowly over 30 minutes to a cold (−70° C.), stirred solution of 4-bromo-2-fluorotoluene (5 g, 26 mmol) in tetrahydrofuran (25 ml). After addition was complete, the mixture was stirred for 15 minutes and a solution of dimethylformamide (2 g, 28 mmol) in tetrahydrofuran (10 ml) was then added over 10 minutes. After addition was complete, the reaction solution was warmed to room temperature over 30 minutes. The reaction was poured into 0.5N aqueous potassium bisulfate (125 ml) and extracted with ethyl ether. The combined organic extracts were dried over sodium sulfate and evaporated to give 3.3 g (90%) of the desired product as an oil. This material was suitable for use without further purification.
Reaction SMILES: [C:1]([C:3]([CH3:9])([CH3:8])[C:4]([NH:6][NH2:7])=O)#[N:2].CCN(CC)CC.Cl.[C:18](=[NH:27])(OC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH3:8][C:3]([C:4]1[NH:6][N:7]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:27]=1)([CH3:9])[C:1]#[N:2]
Reactant: CC(C)(C#N)C(=O)NN
Reactant: COC(=N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C#N)c1nc(-c2ccccc2)n[nH]1
Yield: 65 %

Procedure:
2-Cyano-2-methylpropanehydrazide (100 mg, 0.78 mmol) and Et3N (0.1 mL, 0.86 mmol) were added to a solution of methyl benzimidate hydrochloride (100 mg, 0.58 mmol) in dry MeOH (10 mL), and the mixture was heated to reflux for 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product was purified by column chromatography (silica 60-120 mesh, eluant 15% EtOAc in petroleum ether) to get 2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propanenitrile (80 mg, yield 51%). 1H NMR (300 MHz, MeOD) δ 7.98-7.95 (m, 2H), 7.52-7.50 (m, 3H), 1.82 (s, 6H). MS (ESI) m/z: Calculated for C12H12N4: 212.11. found: 213.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[F:5][C:6]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:7]=1[NH2:8]>C(Cl)(Cl)Cl.O>[F:5][C:6]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:7]=1[N:8]=[C:1]=[S:2]
Reactant: Nc1ccc(I)cc1F
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Fc1cc(I)ccc1N=C=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
Thiophosgene (3.55 mL, 46.4 mmol) was added to a rapidly-stirred mixture of 2-fluoro-4-iodoaniline (10.0 g, 42.2 mmol) in CHCl3 (200 mL) and water (100 mL). The mixture was stirred at r.t. for 16 h. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound as an off-white crystalline solid (11.8 g, quant.). δH (DMSO-d6) 7.87 (1H, dd, J 1.8, 9.5 Hz), 7.63 (1H, ddd, J 1.0, 1.8, 8.4 Hz), 7.25 (1H, dd, J 8.2, 8.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:8]1)=[O:6].C(N(C(C)C)CC)(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41](Cl)[C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)=[CH:37][CH:36]=1>C(Cl)(Cl)(Cl)Cl>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([CH:41]([NH:1][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[C:5]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:8]2)=[O:6])[C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)=[CH:39][CH:40]=1
Reactant: Nc1cccc(C(=O)n2cc(CCCC(=O)O)c3ccccc32)c1
Reactant: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CCCc1cn(C(=O)c2cccc(NC(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c2)c2ccccc12
Yield: 69 %

Procedure:
To a solution of 4-[1-(3-aminobenzoyl)indol-3-yl]butyric acid (1.0 g) and diisopropylethylamine (1.3 g) in carbon tetrachloride (20 ml) was added bis(4-chlorophenyl)methyl chloride (0.84 g). The mixture was refluxed for 6 hours and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (20 ml) and diluted hydrochloric acid (30 ml) and washed with water (30 ml×3). The solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by a column of silica gel to give a yellow solid of 4-[1-[3-[bis(4-chlorophenyl)methylamino]benzoyl]indol-3-yl]butyric acid (1.19 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH2:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]([CH3:48])([CH3:47])[CH:45]=O)[CH2:40][CH2:39]1)[CH3:37].N1CCCC1.Cl[Si](C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:48][C:44]([N:41]4[CH2:40][CH2:39][N:38]([CH2:36][CH3:37])[CH2:43][CH2:42]4)([CH3:45])[CH3:47])[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Reactant: CCN1CCN(C(C)(C)C=O)CC1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCNC1
Product: CCN1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@@H](n3nc(-c4ccc(Oc5ccccc5)cc4F)c4c(N)ncnc43)C2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To the solution of 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-3-oxo-propanenitrile (0.32 mL, 0.57 mmol DCM (20 mL), 2-(4-ethylpiperazin-1-yl)-2-methyl-propanal (211.84 mg, 1.15 mmol) and pyrrolidine (0.14 mL, 1.72 mmol) was stirred at room temperature for 10 minutes then added chloro(trimethyl)silane (0.29 mL, 2.3 mmol). The mixture was allowed to stirred at room temperature for 18 h. The mixture was worked up with saturated NaHCO3 (50 mL) and DCM (50 mL×2), washed with saturated sodium chloride, dried (MgSO4) and concentrated to yield an oil which was purified over silica gel (5%-50% iPA/DCM) to obtain 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-(4-ethylpiperazin-1-yl)-4-methyl-pent-2-enenitrile 265 mg (72.3% yield). MS (pos. ion) m/z: 638 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)(=[O:12])[CH:10]=[CH2:11]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:8][CH2:11][CH2:10][C:9]2=[O:12]
Reactant: C=CC(=O)O
Reactant: Oc1ccc(F)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: O=C1CCOc2ccc(F)cc21
Temperature: 40 °C
Yield: 147.3 %

Procedure:
A 400 ml stainless steel Parr reactor was charged with para-fluorophenol (28.4 grams), acrylic acid (28.8 grams), and an inhibitor phenothiazine (0.02 grams). The system was sealed, evacuated and cooled in dry ice/acetone before the anhydrous hydrogen fluoride (117 grams) was condensed into the system. The mixture was then warmed to 40° C. for one hour thirty minutes with stirring before being heated to 100° C. for four hours thirty minutes. The excess HF was them removed and the system cooled to 0° C. and opened to give 62 grams of brown oil which was washed with D.I. water to give 50 grams of material to be extracted. The 6-Fluoro-4-Chromanone was collected and recrystallized from methanol/water. The HPLC yield was 75%, isolated 52%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([B:9]2[O:13][CH2:12][CH2:11]O2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17]C=1COCOC>>[F:21][C:19]1[CH:18]=[CH:17][C:11]2[CH2:12][O:13][B:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[C:15]=2[CH:20]=1
Reactant: COCOCc1ccc(F)cc1Br
Reactant: N#Cc1cccc(B2OCCO2)c1
Product: N#Cc1cccc(B2OCc3ccc(F)cc32)c1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(3-cyanophenyl)-[1,3,2]-dioxaborolane and 1-bromo-5-fluoro-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15]Br)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH:30][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@H](CCCBr)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(N)(=O)=O
Product: C[C@H](CCCNS(C)(=O)=O)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 89 %

Procedure:
4-chloro-N-(5-chloro-2-fluorophenyl)-N-[4-[(methylsulfonyl)amino]-1(R)-methylbutyl]-benzenesulfonamide was prepared analogous to 4-chloro-N-(2,5-dichlorophenyl)-N-[4-[[4 (methylsulfonyl)methyl]-1-piperidinyl]-1(R)-methylbutyl]benzenesulfonamide by reacting 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[4-bromo-1(R)-methylbutyl]benzenesulfonamide with methanesulfonamide. Yield=89%; MS (ESI+), 483 (M+H)+.
Reaction SMILES: [C:1]12([Li])[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:5](=[CH2:6])[C:2]2([CH3:4])[CH3:3].[Cl-].[Zn+2:13].[Cl-]>CCCCC.C(OCC)C>[C:1]12([Zn:13][C:1]34[CH2:10][CH:7]([CH2:8][CH2:9]3)[C:5](=[CH2:6])[C:2]4([CH3:4])[CH3:3])[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:5](=[CH2:6])[C:2]2([CH3:4])[CH3:3]
Reactant: [Li]C12CCC(C1)C(=C)C2(C)C
Reactant: [Zn+2]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCCCC
Product: C=C1C2CCC([Zn]C34CCC(C3)C(=C)C4(C)C)(C2)C1(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Thiele et al. Anorg. Allg. Chem. Chem. 1988, 561, 73. To a stirred suspension of 18.4 g 1-camphenyllithium in 250 mL n-pentane is added dropwise a solution of 9 g zincchloride in 300 mL diethylether at room temperature (keep the speed of addition in such a way that the solution is boiling smoothly). This reaction mixture is stirred for 3 h and is subsequently allowed to stand overnight. The precipitated LiCl is filtered off and the solvent of the filtrate is completely removed. The residue is solved in n-pentane and remaining LiCl is separated. The solution is the cooled to -78° C. The precipitated crystalls are filtered at low temperature and dried in vacuo. Yield: 12.5 g (60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:14][NH2:15])=[N:10][CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:16](OC(OCC)OCC)(=O)C>CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[N:10]([CH:16]=[N:15][N:14]=3)[CH:11]=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: NNc1ncncc1-c1ccc(Cl)cc1
Solvent: CCCCCC
Product: Clc1ccc(-c2cncn3cnnc23)cc1
Reaction time: 0.38 h

Procedure:
A mixture of 2.0 g. of 5-(4-chlorophenyl)-4-hydrazinopyrimidine is shaken with 10 ml. of diethoxymethyl acetate. The mixture is allowed to stand 15-30 minutes and then is diluted with hexane. The precipitated product (1.81 g: 83%) is collected and recrystallized from ethanol to give the title compound; m.p. 193°-195° C .
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[C:12](=[O:13])[CH:11]=[CH:10][O:9][C:8]=1[CH3:14].[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O>CN(C)C=O>[Si:19]([O:6][C:7]1[C:12](=[O:13])[CH:11]=[CH:10][O:9][C:8]=1[CH3:14])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1occc(=O)c1O
Agent: O=C([O-])O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1occc(=O)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.9 %

Procedure:
A solution of imidazole (Im, 5.45 g, 0.08 mol) in N,N-dimethylformamide (20 ml) is added in an inert atmosphere and dropwise to a solution containing 3-hydroxy-2-methyl-4-pyrone (5.00 g, 0.04 mol) and tert-butyl-dimethylchlorosilane (TBDMSCl, 7.00 g, 0.044 mol) in N,N-dimethylformamide (100 ml). The mixture obtained thereby is maintained stirring at a room temperature for 6 h and then diluted by adding a 5% hydrogen carbonate aqueous solution (150 ml). The mixture obtained thereby is extracted with hexane (6×50 ml); the extracted organic phases are combined, anhydrified on sodium sulphate, and evaporated under vacuum obtaining the desired 3-(tert-butyl-dimethylsilyl)oxy-2-methyl-4-pyrone compound as a colourless crystalline solid (9.61 g).
Reaction SMILES: [N:1]([CH:4]1[CH:10](O)[CH2:9][CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5]1)=[N+:2]=[N-:3].COCCN(S(F)(F)[F:32])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[N:1]([CH:4]1[CH:10]([F:32])[CH2:9][CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: [N-]=[N+]=NC1CCN(C(=O)OCc2ccccc2)CCC1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: [N-]=[N+]=NC1CCN(C(=O)OCc2ccccc2)CCC1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of benzyl 4-azido-5-hydroxyazepane-1-carboxylate (1.0 g, 3.45 mmol) in dry DCM (10 ml) was added deoxo-Fluor® (1.6 mL, 8.62 mmol, 50% in THF) and the mixture was stirred at room temperature for 18 hr. Saturated aqueous NaHCO3 solution was added (20 mL) and the mixture was extracted with DCM (100 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (20 mL), separated, dried over MgSO4 and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (20% EtOAc/isohexane) to give benzyl 4-azido-5-fluoroazepane-1-carboxylate as a mixture of syn and anti isomers as a pale yellow oil (0.76 g).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+]>C(O)(=O)C>[CH2:16]([O:20][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1)[C:17]#[C:18][CH3:19]
Reactant: CC#CCO
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
To 70 ml of N,N-dimethylformamide, 3.00 g (19 mmol) of 6-chloronicotinic acid and 2.00 g (29 mmol) of 2-butyne-1-ol were dissolved, followed by adding 1.80 g (45 mmol) of 60% sodium hydride, stirring at room temperature for 1 hour and stirring at 140° C. for 3 hours. The reaction liquid was then poured in 150 ml of ice water, and acetic acid was added to make pH 5, followed by adding 50 ml of a saturated saline solution. The crystal precipitated was filtered, washed with cold water and hexane and dried to obtain 0.96 g (yield: 26%) of 6-(2-butynyloxy)nicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[CH2:4][NH:5][CH:6]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:7]([O:9][CH3:10])=[O:8].[C:35]([O-])(O)=O.[Na+].CI>CO>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[CH2:4][N:5]([CH3:35])[CH:6]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NCc1c(Cl)cccc1Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)N(C)Cc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To 100 mg of (methyl 2-[(2,6-dichlorobenzyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate) 41 in CH3OH (2.3 ml) are added, at 0° C., NaHCO3 (1 equ.) and CH3I (1 equ.). The reaction is stirred for 1 h at 0° C., and then at room temperature for 2 days. The solvent is evaporated and CH2Cl2 (10 ml) is added to the residue. The solution is washed with water, brine, again water and dried over MgSO4, filtered and evaporated. Due to an incomplete reaction, the protocol is repeated using a tenfold excess of NaHCO3 and CH3I in MeOH (5 ml). After a similar work-up, the residue is purified by silica gel chromatography using hexane/AcOEt 90/10 as eluent to give methyl 2-[(2,6-dichlorobenzyl)(methyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 51.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH2:11])[S:8][C:5]2=[N:6][CH:7]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH:11][C:15]([NH:14][CH2:12][CH3:13])=[O:16])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1nc2cc(Br)cnc2s1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(Br)cnc2s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromothiazolo[5,4-b]pyridin-2-amine IV (1.30 g, 5.55 mmol) in 1,4-dioxane (20.0 mL) was added ethylisocyanate (2.19 mL, 27.07 mmol) and the resulting reaction mixture was heated to 80° C. for 8 h. After the completion of the reaction (TLC monitoring), 1,4-dioxane was distilled off followed by co-distillation with n-hexane (2 times). The residue was then stirred with water at 90° C. for 2 h followed by filtration to obtain the desired product that was further washed with hot water and then dried. The residue was finally washed with ether to obtain the desired product (1.40 g, 83%). 1H NMR (400 MHz, DMSO-d6): δ 1.10 (t, J=7.20 Hz, 3H), 3.20 (quintet, J=7.20 Hz, 2H), 6.76 (br s, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H) and 11.05 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[CH:20]=[CH:19][C:18]4[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=4[C:16]=3[N:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]2[CH:29]=[CH:28][CH:27]=[CH:26][C:13]=23)=[CH:4][CH:3]=1.C1([N:36]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[N:38]=[C:37]2[C:45]2[CH:50]=[CH:49][C:48](B3OC(C)(C)C(C)(C)O3)=[CH:47][CH:46]=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:2]1([N:36]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[N:38]=[C:37]2[C:45]2[CH:46]=[CH:47][C:48]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[C:21]5[CH:20]=[CH:19][C:18]6[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=6[C:16]=5[N:15]=[C:14]5[C:9]=4[CH:10]=[CH:11][C:12]4[CH:29]=[CH:28][CH:27]=[CH:26][C:13]=45)=[CH:4][CH:3]=3)=[CH:49][CH:50]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)OC1(C)C
Reactant: Brc1ccc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1ccc(-n2c(-c3ccc(-c4ccc(-c5c6ccc7ccccc7c6nc6c5ccc5ccccc56)cc4)cc3)nc3ccccc32)cc1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
6 (2.1 g, 4.8 mmol), 1-phenyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-benzo[d]imidazole (3.8 g, 9.6 mmol), Palladium tetrakis triphenylphoshine (830 mg) and 17 mL of a 1M potassium carbonate solution in water were introduced in a flask together with 35 mL degassed toluene. This mixture is stirred at 80° C. during 36 hours before being let cooled to room temperature and filtered. The solid is then dissolved in dichloromethane (600 mL) and filter over a Celite pad. The volatiles are removed by rotary evaporation and the solid is then dried overnight in a vacuum oven.
Reaction SMILES: [Na].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([O:26][CH2:27][CH2:28][O:29][C:30]4[N:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=4)=[N:13][N:14]([CH3:25])[C:15]=3[N:16](S(C)(=O)=O)[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3]1>CO.ClCCl.[Cl-].[NH4+]>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([O:26][CH2:27][CH2:28][O:29][C:30]4[N:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=4)=[N:13][N:14]([CH3:25])[C:15]=3[NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1N(S(C)(=O)=O)S(C)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1NS(C)(=O)=O
Yield: 77 %

Procedure:
An aqueous solution of sodium hydroxyde (1M, 0.91 ml) was added at room temperature to a solution of N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-N-(methylsulfonyl)methane sulfonamide (Preparation 49) (50 mg) in a mixture of methanol (1 ml) and dichloromethane (0.3 ml). After 1 h the reaction was diluted with an aqueous saturated solution of ammonium chloride (4 ml) and the mixture was extracted with dichloromethane (3*5 ml). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The pale yellow oil was purified by preparative TLC (silica) eluted with dichloromethane:methanol (95:5) to yield the title compound as a colourless oil (33 mg)
Reaction SMILES: [NH:1]([C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:18][C:12]=2[CH2:11]1)=[S:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:24][S:9]/[C:8](=[N:1]\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)/[N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:18][C:12]=2[CH2:11]1
Reactant: CCOC(=O)c1nc2c(s1)CN(C(=S)Nc1ccccc1)CC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1nc2c(s1)CN(/C(=N/c1ccccc1)SC)CC2
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 5-(anilinocarbonothioyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate obtained in step I (1 eq) in acetone, K2CO3 (1.2 eq) was added and the reaction mixture was stirred for 15 min. To this, iodomethane (1.2 eq) was added and the reaction was continued at room temperature for 5 h. Solvent was evaporated and the residue was diluted dichloromethane. It was then washed with water and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the ethyl 5-[(Z)(methylthio)(phenylimino)methyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate.