Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[C:10]2[CH:17]=[CH:18][C:19]([C:21]#[N:22])=[CH:20][C:9]=2[NH:8]1>>[Cl:3][C:7]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[C:10]2[CH:17]=[CH:18][C:19]([C:21]#[N:22])=[CH:20][C:9]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc2c(c1)[nH]c(=O)c1ccncc12
Product: N#Cc1ccc2c(c1)nc(Cl)c1ccncc12

Procedure:
Phosphorus oxychloride (2 mL) was added to the 5-oxo-5,6-dihydrobenzo[c][2,6]naphthyridine-8-carbonitrile (150 mg, 0.66 mmol). The mixture was heated reflux for 3 hours at which time LCMS analysis indicated the absence of any starting material. Volatiles were removed under vacuum and the crude product was dissolved in dichloromethane, washed with brine and saturated aqueous sodium bicarbonate and dried over sodium sulfate. After concentrating under vacuum, the crude product was triturated with ethyl acetate and hexanes to give 5-chlorobenzo[c][2,6]naphthyridine-8-carbonitrile (125 mg). LCMS (ESI) 240.3 (M+1)+.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:24])[NH:6][C:7]1[CH:13]=[CH:12][C:11]([S:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])=[CH:10][C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH3:25][O:26][C:27]([N:29]=[C:30]=[S:31])=[O:28]>O1CCOCC1>[C:1]([NH:4][C:5](=[O:24])[NH:6][C:7]1[CH:13]=[CH:12][C:11]([S:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])=[CH:10][C:8]=1[NH:9][C:30]([NH:29][C:27]([O:26][CH3:25])=[O:28])=[S:31])(=[O:3])[CH3:2]
Reactant: COC(=O)N=C=S
Reactant: CC(=O)NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1N
Solvent: C1COCCO1
Product: COC(=O)NC(=S)Nc1cc(S(=O)(=O)Oc2ccccc2)ccc1NC(=O)NC(C)=O
Temperature: 25 °C

Procedure:
17.5 g of 2-(3-acetylureido)-5-phenoxysulfonylaniline and 15 ml of methoxycarbonyl isothiocyanate in 150 ml of dioxane are heated at 80° C. for 5 minutes, and then stirring is continued without heating. After slowly cooling down to room temperature, the dioxane is distilled out under reduced pressure. The residue is dissolved in dimethylformamide, the solution is treated with active charcoal and evaporated and then methanol is added. After cooling down, the precipitate is filtered off with suction and washed with methanol and diisopropyl ether. Melting point 215° C., decomposition.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:27])[C@@H:8]([NH:19]C(OC(C)(C)C)=O)[CH2:9][CH2:10][CH2:11][NH:12][CH2:13][N:14]=[N:15][N+:16]([O-:18])=[O:17].Cl.[Cl:29]CCl>C1COCC1.O1CCOCC1>[ClH:29].[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:27])[C@@H:8]([NH2:19])[CH2:9][CH2:10][CH2:11][NH:12][CH2:13][N:14]=[N:15][N+:16]([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)Nc1nccs1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)Nc1nccs1
Reaction time: 3 h

Procedure:
(2S)-2-tert-Butoxycarbonylamino-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide (2.28 g, 5.68 mmol) is dissolved in 5 mL THF and 5 mL 4 N HCl in dioxane. After 3 h, dichloromethane is added and the mixture is filtered. The semisolid is collected and is treated with methanol—toluene and concentrated in vacuo; this process is repeated several times to afford 1.63 g of (2S)-2-amino-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide hydrochloride as a solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH:17]=1.[Li]CCCC.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].O>C1COCC1>[CH2:37]([O:36][C:34]([C:15]1[N:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)[CH:17]=[C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[N:14]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2c(-c3ccccc3)noc2C)cn1-c1ccc(C(F)(F)F)cc1
Temperature: -25 °C
Yield: 20.2 %

Procedure:
To a solution of 5-methyl-3-phenyl-4-[1-(4-trifluoromethyl-phenyl)-1H-imidazol-4-yl]-isoxazole (950 mg, 2.6 mmol) in THF (50 mL) at −78° C. was added BuLi (1.6 M in hexane, 2.4 mL, 3.9 mmol) and the resulting mixture allowed to warm up to −25° C. over 20 min and then re-cooled to −78° C. Then ethyl chloroformate (474 mg, 4.4 mmol) was added and the resulting mixture allowed to warm up to −25° C. over 3 h and then warmed up to 0° C. whereupon water was added. The reaction mixture was then extracted with ethyl acetate and the combined organic layers were then washed with a saturated solution of sodium hydrogen carbonate, brine and then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (232 mg, 18%) which was obtained as an off-white foam. MS: m/e=442.5 [M+H]+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:13][C:14]1[N:19]=[C:18]([C:20]2[C:21]([CH3:56])=[CH:22][C:23]([CH3:55])=[C:24]([CH:54]=2)[C:25]([NH:27][CH2:28][C:29]2([CH2:33][NH:34][C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:32][O:31][CH2:30]2)=[O:26])[CH:17]=[C:16](Cl)[N:15]=1.Cl>CN(C)C=O>[NH2:13][C:14]1[N:15]=[C:16]([S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH:17]=[C:18]([C:20]2[CH:54]=[C:24]([C:25](=[O:26])[NH:27][CH2:28][C:29]3([CH2:33][NH:34][C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:32][O:31][CH2:30]3)[C:23]([CH3:55])=[CH:22][C:21]=2[CH3:56])[N:19]=1
Reactant: Cc1cc(C)c(-c2cc(Cl)nc(N)n2)cc1C(=O)NCC1(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)COC1
Reactant: O=C(O)CCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2cc(SCCC(=O)O)nc(N)n2)cc1C(=O)NCC1(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)COC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
3-Mercaptopropionic acid (84 μl, 0.937 mmol) and cesium carbonate (316 mg, 0.970 mmol) were added to an N,N-dimethylformamide (1.0 ml) solution of 5-(2-amino-6-chloropyrimidin-4-yl)-2,4-dimethyl-N-{3-[(tritylamino)methyl]oxetan-3-ylmethyl}benzamide (119 mg, 0.192 mmol) obtained in Step 2 above. The resulting mixture was stirred at 80° C. for 1.5 hour. The reaction solution was slightly acidified with 1N hydrochloric acid, and the precipitated solid was collected by filtration. The separated solid was washed with water, and then dried under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=15:1) to yield 3-{2-amino-6-[2,4-dimethyl-5-({3-[(tritylamino)methyl]oxetan-3-ylmethyl}carbamoyl)phenyl]pyrimidin-4-ylsulfanyl}propanoic acid (77 mg) as a white solid material.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])/[CH3:4].[NH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][CH3:29]>>[CH2:28]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[CH2:22][NH:21][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])/[CH3:4])=[CH:20][CH:19]=1)[CH3:29]
Reactant: CC(C)=CCC/C(C)=C\COc1ccc(C(=O)O)cc1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccc(OC/C=C(/C)CCC=C(C)C)cc1
Yield: 30 %

Procedure:
In a manner identical to Example 15, 4-neryloxybenzoic acid(1.64 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.84 ml), thereby yielding 0.69 g(30%) of the aimed compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:31])[C@:7]1([OH:30])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([O:26][CH:27]=[O:28])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:29])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].[CH2:32]([O:34][CH2:35]OCC)[CH3:33].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6](=[O:31])[C@:7]1([O:30][CH2:35][O:34][CH2:32][CH3:33])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([O:26][CH:27]=[O:28])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:29])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CCOCOCC
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](OC=O)C[C@@]21C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCOCO[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](OC=O)C[C@@]21C
Reaction time: 2.5 h

Procedure:
5.0 g. of 21-acetoxy-11β-formyloxy-17α-hydroxy-1,4-pregnadiene-3,20-dione is dissolved in 150 ml. of methylene chloride and 30 ml. of formaldehyde diethylacetal and cooled to 0° C. Under agitation, a mixture of 5 g. of phosphorus pentoxide and 10 g. of kieselguhr is inroduced, and the mixture is stirred for 2.5 hours in an ice bath, whereafter it is filtered, washed with methylene chloride, and brought to pH 9 with triethylamine. After the solvent has been distilled off, 10.5 g. of crude 21-acetoxy-17α-ethoxymethoxy-11β-formyloxy-1,4-pregnadiene-3,20-dione is obtained as a semisolid mass.
Reaction SMILES: [C:1]([C:4]1([NH:37]C(=O)OC(C)(C)C)[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[C:24]4[C:19](=[CH:20][N:21]=[C:22]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:23]=4)[N:18](C4CCCCO4)[N:17]=3)[N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].Cl>CO.O1CCOCC1>[NH2:37][C:4]1([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[C:24]4[C:19](=[CH:20][N:21]=[C:22]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:23]=4)[NH:18][N:17]=3)[N:11]=2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(C(N)=O)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)C1(N)CCN(c2cccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)CC1
Reaction time: 18 h
Yield: 60.3 %

Procedure:
A mixture of 45 mg (0.08 mmol) of tert-butyl 4-carbamoyl-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate in 3 ml of methanol and 12 ml of 4 N solution of HCl in dioxane was stirred for 18 hours. The mixture was concentrated in vacuum, the residue purified via reverse phase HPLC using a gradient of MeCN in water with 0.1% HCOOH to afford 20 mg (43%) of 229. ESI MS m/z 415.2 (M+1). 1H NMR (400 MHz, DMSO): 9.22 (d, J=5.7 Hz, 2H), 8.94 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.40-8.32 (m, 4H), 7.67 (t, J=7.9 Hz, 1H), 7.54 (dd, J=8.0, 4.8 Hz, 1H), 7.46 (d, J=7.4 Hz, 1H), 6.95 (s, 1H), 6.90 (d, J=8.5 Hz, 1H), 4.20 (d, J=13.2 Hz, 1H), 3.50 (t, J=11.4 Hz, 1H), 2.06 (td, J=13.0, 4.2 Hz, 1H), 1.48 (d, J=13.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([I:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Cl:18][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[I:17])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1
Reactant: Fc1ccc(-n2ncc3c(I)ccnc32)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(-n2nc(Cl)c3c(I)ccnc32)cc1
Reaction time: 8 h

Procedure:
To a solution of Intermediate 2A (33.9 mg, 0.1 mmol) in DMF (Volume: 1 mL) under argon at room temp was added N-chlorosuccinimide (107 mg, 0.800 mmol). The reaction mixture was allowed to stir overnight. The reaction mixture was diluted with ethyl acetate and washed (2×15 mL) with 10% LiCl, once with brine, dried over Na2SO4, filtered and concentrated. The crude product was dissolved in a small amount of dichloromethane and charged to a 4 g silica gel cartridge which was eluted with a 20 min gradient from 0% to 100% of ethyl acetate in dichloromethane. The resulting brown solid (23 mg, 61.6%) was determined to be the desired material by 1HNMR and LCMS. MS (ES): m/z=274.0 [M+H]+. 1H NMR (400 MHz, CCl3D) δ ppm 8.58-8.60 (1 H, m), 8.24 (1 H, s), 8.14-8.20 (2 H, m), 7.18-7.26 (2 H, m).
Reaction SMILES: C([O:5][C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])[CH3:8])(C)(C)C.F[C:35](F)(F)C(O)=O.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:6]([N:7]([CH3:8])[CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])(=[O:5])[CH3:35]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(C)CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{2-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-ethyl}-methyl-carbamic acid tert-butyl ester (65 mg, 0.14 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed in vacuo. To the residue were added CH2Cl2 (3 mL), triethylamine (0.2 mL, 1.4 mmol), and acetic anhydride (0.070 mL, 0.72 mmol), and the resulting mixture was stirred for 16 h. The mixture was diluted with CH2Cl2 (50 mL) and washed with 0.1 M HCl, saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was dissolved in MeOH (3 mL) and treated with 2.9 mL of 0.5 M NaOMe solution. After stirring for 1 h at r.t., 1 M HCl was added to acidify the mixture. The resulting suspension was extracted with EtOAc, and the organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 32 mg of the title compound. MS: (+) m/z 395.32 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][C:9]=1[OH:23])=[O:6].[OH-].[NH4+:26]>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2])=[C:9]([OH:23])[CH:10]=1
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1O
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1O
Yield: 23 %

Procedure:
Prepared in analogy to example 3 from N-[4-(3-fluoro-benzyloxy)-2-hydroxy-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=23%. Colorless solid. MS: m/e=319.4 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[F:9].[Li+].CC([N-]C(C)C)C.[CH3:18][S:19]SC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([S:19][CH3:18])[C:3]=1[F:9]
Reactant: CSSC
Reactant: Fc1cc(Cl)ccc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1c(Cl)ccc(Br)c1F
Temperature: -20 °C
Yield: 94 %

Procedure:
A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol) in THF (50 mL) was slowly added to LDA (0.125 mol) in THF (600 mL) at −50° C. After addition, the solution was warmed to −20° C. and then cooled to −50° C. A solution of dimethyldisulfide (18.8 g, 0.20 mol) in THF (50 mL) was then slowly added and the mixture was warmed to ambient temperature. The reaction was quenched with water (200 mL), extracted with ethyl acetate (2×150 mL), and the combined organic phases dried and concentrated. The residual red oil was purified by chromatography (5% ethyl acetate in hexanes) to give 1-bromo-4-chloro-3-methylthio-2-fluorobenzene (23.9 g, 0.094 mol): 1H NMR (CDCl3): δ 7.40 (m, 1H), 7.15 (dd, 1H), 2.50 (s, 3H).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH3:11]
Reactant: COC(=O)c1ccc(C(C)CCOC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1ccc(C(C)CCO)cc1
Reaction time: 12 h
Yield: 98.8 %

Procedure:
To the solution of methyl 4-(4-(tetrahydro-2H-pyran-2-yloxy)butan-2-yl)benzoate (501.8 mg 1.72 mmol) in methanol (60 mL) was added p-toluenesulfonic acid (592 mg, 3.44 mmol). the solution was stirred for 12 hours, then the solvent was remove and dissolved in dichloromethane (50 ml) and washed water, dried with sodium sulfate, concentrated to give methyl 4-(4-hydroxybutan-2-yl)benzoate (354 mg, 99%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([N:10]2[C:14]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[S:21](=[O:24])(=[O:23])[CH2:22][C:13]=3[C:12]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[N:11]2)[CH2:5]1.[NH3:33]>CC#N>[N:27]1([C:25]([C:12]2[C:13]3[CH2:22][S:21](=[O:24])(=[O:23])[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]=3[N:10]([CH:6]3[CH2:7][CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH2:33])[CH2:5]3)[N:11]=2)=[O:26])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: N
Reactant: O=C(c1nn(C2CCCN(CCCl)C2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Solvent: CC#N
Product: NCCN1CCCC(n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)C1
Temperature: 135 °C
Reaction time: 0.25 h

Procedure:
To a solution of enantiomer B of 1-[1-(2-chloroethyl)piperidin-3-yl]-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (90 mg; 0.19 mmol; 1.00 eq.) in CH3CN (0.90 ml) is added aq ammonia (181.88 μl; 2.82 mmol; 15.00 eq.) and the reaction is stirred at 135° C. for 15 min under microwave irradiation which after purification by MD-Autoprep affords the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.05 (d, J=7.8 Hz, 1H), 7.96 (t, J=7.1 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.75 (t, J=7.4 Hz, 1H), 4.79 (q, J=16.2 Hz, 3H), 3.90 (s, 2H), 3.66 (s, 6H), 3.15 (d, J=9.7 Hz, 2H), 2.90 (q, J=13.0 Hz, 3H), 2.73-2.53 (m, 2H), 2.27-2.02 (m, 2H), 2.00-1.59 (m, 3H). MS (ESI+): 460.3. HPLC (max plot) 55.4%; Rt 2.09 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10]O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.P(Br)(Br)[Br:13].O>O1CCCC1>[Br:13][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: OCc1ccc2c(c1)CCO2
Reactant: BrP(Br)Br
Solvent: O
Solvent: C1CCOC1
Product: BrCc1ccc2c(c1)CCO2
Reaction time: 0.33 h
Yield: 100.4 %

Procedure:
To a solution of (2,3-dihydrobenzofuran-5-yl)methanol (29.0 g, 0.193 mol) in tetrahydrofuran (150 mL) was added phosphorous tribromide (34.8 g, 0.129 mol) under ice/salt-cooling. The mixture was stirred for 20 minutes and then poured into water. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated to afford the title compound (yield 27.6 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.[Cl-]>C(N(CC)CC)C>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2ccc(Cl)cc2)c(C(N)=O)cc1OC

Procedure:
A mixture of 13.7 g of 2-amino-4,5-dimethoxybenzamide, 8.1 g of triethylamine, 13.8 g of 4-chlorobenzoyl chloride and 300 ml of methylene. chloride was stirred for 2 h without cooling. The precipitate was filtered off with suction, stirred with water, filtered off with suction and dried under reduced pressure. Yield: 22.5 g. M.p.: 243° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10](I)[C:11]([NH2:14])=[N:12][CH:13]=1.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>O1CCOCC1>[Br:7][C:8]1[CH:9]=[C:10]([C:21]2[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(Br)cnc2N)cn1
Temperature: 120 °C
Reaction time: 14 h

Procedure:
I2 (8.81 g, 34.7 mmol, 1.2 equiv.) was added to a solution of 5-bromopyridin-2-amine (5.00 g, 28.9 mmol) in DMSO (30 mL), and the resulting mixture was stirred at 100° C. for 4 h. After standing at 25° C. for 12 h, the reaction mixture was poured onto a saturated Na2S2O5 aqueous solution (20 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, EtOAc 15 to 25%) providing 5-bromo-3-iodopyridin-2-amine (4.00 g, 46%) as a pale yellow solid. H1 NMR (300 MHz, CDCl3): δ 8.07 (s, 1H), 7.98 (s, 1H) and 5.05 (bs, 2H). K2CO3 aqueous solution (1 M, 6.8 mL) was added to a suspension of 5-bromo-3-iodopyridin-2-amine (2.00 g, 6.69 mmol), 6-methoxypyridin-3-ylboronic acid (1.12 g, 7.32 s mmol, 1.1 equiv.), and Pd(PPh)3 (380 mg, 5 mol %) in dioxane (20 mL) under N2. The reaction mixture was stirred at 120° C. for 14 h, poured onto H2O (65 mL) and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, EtOAc 30 to 40%) providing intermediate 5-bromo-3-(6-methoxypyridin-3-yl)pyridin-2-amine (1′) (Formula iv) (993 mg, 53%) as a pale yellow solid.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:30]3[CH:31]=[CH:26][CH:27]=[C:28]([S:32]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)(=[O:34])=[O:33])[CH:29]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(c1cccc(Br)c1)N1CCOCC1
Product: O=S(=O)(c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1)N1CCOCC1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-(3-bromo-benzenesulfonyl)-morpholine (example B.31) (275 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (390 mg, 68%). MS (ISP) 563.4 [(M+H)+]; mp 175-176° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[S:14][CH2:15][C:10]=3[C:9]([C:20]([OH:22])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:25])=O>O1CCOCC1>[C:1]1([N:7]2[C:11]3[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[S:14][CH2:15][C:10]=3[C:9]([C:20]([Cl:25])=[O:22])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C(Cl)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2

Procedure:
1,4-Dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carboxylic acid (2 g) is reacted with thionyl chloride (1 ml) in dioxane (40 ml) at reflux temperature for 2 hours. After cooling the solution is evaporated to dryness in vacuo to give 1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carbonyl chloride as crystalline residue. The crude product is dissolved in anhydrous dioxane (15 ml) and reacted for 2 h under stirring at room temperature with the carbanion obtained by treatment of cyanacetic acid, 2-morpholinomethylbenzylamide (1.95 g) with 50% sodium hydride (0.39 g) in anhydrous dioxane/dimethylformamide 9:1 (20 ml) at room temperature.