Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:30])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:17]=[C:16]4[CH:28]=O)[CH:10]=[N:9][CH:8]=2)[CH2:3][CH2:2]1.[N:31]1[CH:36]=[C:35]([NH2:37])[C:34]([NH2:38])=[C:33]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:32]=1.[S]>CN(C=O)C>[CH:1]1([CH2:4][NH:5][C:6](=[O:30])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:17]=[C:16]4[C:28]3[NH:37][C:35]4[CH:36]=[N:31][CH:32]=[C:33]([C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)[C:34]=4[N:38]=3)[CH:10]=[N:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(-c3cncc(C(=O)NCC4CC4)c3)cc12
Reactant: Nc1cncc(-c2cccnc2)c1N
Agent: [S]
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)c1cncc(-c2ccc3c(c2)c(-c2nc4c(-c5cccnc5)cncc4[nH]2)nn3C2CCCCO2)c1
Temperature: 4 °C
Yield: 23 %

Procedure:
A solution of N-(cyclopropylmethyl)-5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide (XXXI) (0.404 g, 1.0 mmol), 3,3′-bipyridine-4,5-diamine (XV) (186 mg, 1.0 mmol) and sulfur (35 mg, 1.1 mmol) in dry DMF (10 mL) was heated at 140° C. overnight. The reaction was cooled and evaporated under vacuum. The residue was suspended in water, sonicated and filtered. The solid was washed with cold water and dried under vacuum. The crude product was dissolved in DCM and cooled to 4° C. overnight to get N-(cyclopropylmethyl)-5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide (XXXII) as a brown solid (130 mg, 0.23 mmol, 23% yield). 1H NMR (DMSO-d6) δ ppm 0.19-0.37 (m, 2H), 0.36-0.58 (m, 2H), 0.97-1.115 (m, 1H), 1.67 (br, 2H), 2.14 (d, J=9.98 Hz, 2H), 2.40-2.46 (m, 1H), 3.20-3.33 (m, 3H), 3.75-4.14 (m, 2H), 6.13 (d, J=8.29 Hz, 1H), 7.60 (dd, J=7.82, 4.80 Hz, 1H), 7.92-8.12 (m, 3H), 8.20 (d, J=8.67 Hz, 1H), 8.55-8.67 (m, 2H), 8.94 (br s, 3H), 9.06 (d, J=1.88 Hz, 1H), 9.19 (d, J=1.87 Hz, 1H); ESIMS found C33H30N8O2 m/z 571 (M+H).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.CN([CH:16]=[O:17])C.O>CCOCC>[F:6][C:7]1[C:8]([CH:16]=[O:17])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Fc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: O=Cc1ncccc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 11.1 %

Procedure:
n-Butyl lithium (1.6 M in hexanes, 6.86 mL, 11.0 mmol) was added to a stirred solution of 1,4-diazobicyclo[2.2.2]-octane (1.23 g, 11.0 mmol) in dry Et2O (55 mL) at −78° C. under N2. The reaction was warmed to −20° C. and stirred for 1 h. The reaction was cooled to −78° C. and a solution of 3-fluoropyridine (1.07 g, 11.0 mmol) in Et2O (5.5 mL) was added dropwise via cannula. The reaction was warmed to −60° C. and stirred for 1 h after which time a yellow precipitate appeared. DMF (803 mg, 847 μL, 12.1 mmol) was added dropwise and the reaction was gradually warmed to −20° C. over 4 h. Water (20 mL) was added and the mixture was extracted with Et2O (3×40 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-60% EtOAc in hexanes gradient) to afford 3-fluoropyridine-2-carbaldehyde (152.3 mg, 11%). Rf=0.23 (20% EtOAc/hexanes). LCMS calc.=126.0; found=125.9 (M+1)+. 1H NMR (500 MHz, CDCl3): δ 10.14 (d, J=2.4 Hz, 1H); 8.57 (m, 1H); 7.57-7.53 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([OH:19])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>C1(C)C=CC=CC=1>[CH2:24]([N:26]([CH2:27][CH3:28])[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:19])[CH3:25]
Reactant: CCNCC
Reactant: O=C(O)c1nc(-c2ccccc2)c2ccccc2n1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1nc(-c2ccccc2)c2ccccc2n1

Procedure:
Operations are carried out as for Example 19, starting from 2.5 g of 4-phenyl quinazoline 2-carboxylic acid, 10 ml of thionyl chloride 25 ml of toluene and 25 ml of diethylamine. 1.27 g of N,N-diethyl 4-phenyl quinazoline 2-carboxamide, melting at 101° C., is obtained.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Pb+2:5].[C:6]([O-:9])(=[O:8])[CH3:7].[CH:10]1[CH:15]=[C:14]2[CH:16]=C[CH:18]=[C:19](C([O-])=O)[C:13]2=[CH:12][CH:11]=1.[K+]>O>[CH:11]1[CH:12]=[C:13]2[C:14]([CH:16]=[C:2]([C:1]([O-:4])=[O:3])[CH:18]=[CH:19]2)=[CH:15][CH:10]=1.[CH:11]1[CH:12]=[C:13]2[C:14]([CH:16]=[C:7]([C:6]([O-:9])=[O:8])[CH:18]=[CH:19]2)=[CH:15][CH:10]=1.[Pb+2:5]
Reactant: CC(=O)[O-]
Reactant: O=C([O-])c1cccc2ccccc12
Agent: [K+]
Agent: [Pb+2]
Solvent: O
Product: O=C([O-])c1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
On the other hand, 38 g of stannous chloride, 26 g of lead acetate and 200 g of water were charged into a 500 ml beaker equipped with a stirrer and the metal salts were dissolved into the water with stirring. This aqueous solution of the metal salts was added to the aforesaid aqueous solution of potassium naphthenate and a double decomposition reaction was then carried out for 1 hour at 30° C. The reaction mixture was dehydrated, dried and then extracted with toluene. The residue was heated under a reduced pressure of 10 mm Hg to distill off the toluene whereby stannous and lead naphthenates were obtained which had a tin content of 13.2% by weight and a lead content of 9.2% by weight.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[Br:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42](Cl)=[O:43]>CCCCCC>[Br:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]3)=[CH:6][CH:7]=1)=[O:43]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1)c1cccc(Br)c1
Reaction time: 1 h
Yield: 29.2 %

Procedure:
To a 200 mL three-neck flask was added 5.0 g (12 mmol) of 9-(4-bromophenyl)-10-phenylanthracene. The air in the flask was replaced with nitrogen. Then, 65 mL of tetrahydrofuran was added thereto, and the temperature of the mixture was set to −80° C. Into this solution was dripped 8.1 mL (13 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) with a syringe. After that, this solution was stirred at the same temperature for 1 hour. Then, 2.8 g (13 mmol) of 3-bromobenzoyl chloride was added to this solution, and the mixture was stirred for 18 hours while its temperature was returned to room temperature. Then, an organic substance was extracted from the aqueous layer of this mixture with ethyl acetate, and the solution of the extract and the organic layer were combined and washed with a saturated aqueous sodium chloride solution. The organic layer was dried with magnesium sulfate. Then, this mixture was gravity filtered. The obtained filtrate was concentrated to give a solid. The obtained solid was purified by silica gel column chromatography (with a developing solvent of hexane and toluene in a 5:1 ratio) to give 1.8 g of a light-yellow solid in a yield of 28%. A reaction scheme of the above synthesis method is illustrated in the following (H-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[NH:40][C:39]2=[O:47])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([N:32]3[CH2:33][CH2:34][CH:35]([N:38]4[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[NH:40][C:39]4=[O:47])[CH2:36][CH2:37]3)=[O:23])=[CH:17][C:9]1=2
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1,3-dihydro-1-(4-piperidinyl)benzoimidazol-2-one as in General Procedure 10 to give the title compound. LCMS: m/z=647.02 (M+H+); retention time=0.83 minutes.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(C(C)C)CC)(C)C.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[O:36])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccccn2)CC1
Yield: 80.1 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.064 g, 0.22 mmol) and diisopropylethylamine (0.089 g, 0.69 mmol) in methylene chloride stirring at 0° C. was added picolinoyl chloride hydrochloride (0.043 g, 0.24 mmol) at room temperature. After 2 h the reaction mixture was concentrated under reduced pressure and the residue purified by flash column chromatography (silica gel, 95:5 to 90:10 dichloromethane/methanol) to provide (4-(2-tert-butylphenyl)piperazin-1-yl)(pyridin-2-yl)methanone (0.057 g, 80%) as a brown solid, mp 140-145° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:11]1[CH:12]=[C:13]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:14]([O:28][CH3:29])=[C:15]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([OH:26])[CH:20]=2)[CH:16]=1)([CH3:10])([CH3:9])[CH3:8].Cl[C:36]1[N:41]=[CH:40][N:39]=[C:38]([C:42]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)=[O:43])[CH:37]=1.O>CN(C)C=O>[C:7]([C:11]1[CH:12]=[C:13]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:14]([O:28][CH3:29])=[C:15]([NH:17][C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH:20]=2)[O:26][C:36]2[N:41]=[CH:40][N:39]=[C:38]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]3)=[O:43])[CH:37]=2)=[O:27])[CH:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)ncn2)CC1
Reactant: COc1c(NC(=O)c2ccc(C)c(O)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(NC(=O)c2ccc(C)c(Oc3cc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)ncn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 144 h

Procedure:
75 mg potassium-tert-butoxide are added at ambient temperature under an argon atmosphere to 225 mg N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-hydroxy-4-methyl-benzamide in 3 ml N,N-dimethylformamide. After ten minutes 210 mg tert-butyl 4-(6-chloro-pyrimidin-4-carbonyl)-piperazine-1-carboxylate are added, and the reaction mixture is stirred for six days at ambient temperature. For working up the reaction mixture is mixed with water and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (50:50→20:80).
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]#[N:11])C(OCC)=O)#[N:2].N1C=CC=CC=1.F[B-](F)(F)F.[C:23]1([N+:29]#[N:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[C:23]1([N:29]=[N:30][CH:3]([CH2:9][C:10]#[N:11])[C:1]#[N:2])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#[N+]c1ccccc1
Reactant: CCOC(=O)C(C#N)CC#N
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: c1ccncc1
Product: N#CCC(C#N)N=Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
A solution of ethyl 2,3-dicyanopropanoate (1.58 g, 10.38 mmol) in methanol (52 mL) and pyridine (2.52 mL, 31.14 mmol) was cooled to 10° C. in an ice bath. Benzenediazonium tetrafluoroborate was added portion-wise over 20 minutes at 10° C. and the reaction stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and partitioned between DCM and water. The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound (2.8 g, 28%). The crude product was taken on directly to the next step.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:19][C:18]3[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1cccc2c(Cl)ccnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc3c(Cl)ccnc23)cc1
Temperature: 80 °C
Yield: 88.9 %

Procedure:
A mixture of compound 22 (3.20 g, 17.82 mmol), p-methoxybenzyl chloride (8.37 g, 53.45 mmol), K2OC3 (7.38 g, 53.45 mmol), and n-Bu4NI (1.65 g, 4.45 mmol) in anhydrous DMF (20 mL) was heated at 80° C. for 10 hours. The reaction mixture was extracted with ethyl acetate (3×100 mL), washed with water, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography (Hexane/EtOAc, 3:2) to give 4.75 g (89%) of 23 as yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.81 (s, 3H), 5.38 (s, 2H), 6.78-6.98 (m, 2H), 7.13 (d, 1H, J=7.6 Hz), 7.34-7.60 (m, 4H), 7.80 (d, 1H, J=8.8 Hz), 8.76-8.88 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.[CH3:26][O:27][C@H:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH2:29][C@H:28]([O:27][CH3:26])[CH3:32])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CO[C@H](C)CCN
Agent: Cl
Product: CO[C@H](C)CCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-3-methoxybutan-1-amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (d, J=6.32 Hz, 3 H) 1.58-1.79 (m, 2 H) 2.43 (s, 3 H) 3.24 (s, 3 H) 3.30-3.42 (m, 3 H) 7.66 (dd, J=7.83, 1.26 Hz, 1 H) 7.73 (s, 1 H) 7.77 (br. s., 1 H) 8.18 (br. s., 1 H) 8.29-8.59 (m, 2 H) 8.68 (t, J=5.31 Hz, 1 H) 8.87-8.94 (m, 1 H) 13.17 (br. s., 1 H); ESI-MS m/z [M+H]+ 406.2.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[C:6]([C@@H:8]2[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)[CH:7]=1.[Cl:30][C:31]([O:33][CH3:34])=[O:32].Cl>N1C=CC=CC=1>[ClH:30].[CH:27]([S:24]([C:5]1[CH:4]=[CH:3][C:2]([C:31]([O:33][CH3:34])=[O:32])=[CH:7][C:6]=1[C@H:8]1[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:10][NH:9]1)(=[O:25])=[O:26])([CH3:28])[CH3:29]
Reactant: COC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1c1cc(N)ccc1S(=O)(=O)C(C)C
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(S(=O)(=O)C(C)C)c([C@@H]2NCC[C@@H]2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.1 %

Procedure:
To 61A (0.09 g, 0.21 mmol) in pyridine (1 mL) at 0° C. was added methyl chloroformate (32 μL, 0.42 mmol). After 2.0 h stirring at rt the reaction was acidified with 1M HCl to pH 3-4. The product was extracted with ethyl acetate and was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was redissolved in ethyl acetate (1.5 mL) and hydrogen chloride (2 mL, 4M in dioxane) was added. The reaction was stirred for 3 h at rt. The solvent was removed and placed on the lyophilizer to give 0.11 g solid 61C. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.22-1.40 (m, 6H) 2.43-2.60 (m, 1H) 2.62-2.80 (m, 1H) 3.42 (s, 3H) 3.45-3.65 (m, 2H) 3.67-3.77 (m, 1H) 3.78 (s, 3H) 3.83-3.96 (m, 1H) 5.84 (d, J=8.56 Hz, 1H) 7.55-7.67 (m, 1H) 7.81-7.90 (m, 1H) 7.94 (d, J=8.80 Hz, 1H).
Reaction SMILES: [C:1]([O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)[CH3:2].[NH2:20]C(N)=S>CN(C)C=O>[CH3:2][C:1]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:20]=1
Reactant: NC(N)=S
Reactant: CC(=O)OC(C(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 160 °C

Procedure:
0.2 g of the above 2-oxo-1,2-diphenylethyl acetate is dissolved in 10 ml of dimethylformamide in a reactor. 0.12 g of thiourea (2 eq.) is subsequently added and the reaction mixture is left to react at reflux (160° C.) for 10 hours. The reaction mixture is extracted using dichloromethane and then washed with water 3 times. The organic phase is recovered after separating by settling, dried over sodium sulphate, filtered and then concentrated to dryness under vacuum. The oil obtained is subsequently purified on a column of silica gel (elutent: dichloromethane).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH2:12][C@H:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:18]([O:23][CH3:24])(=[O:22])[C@H:19]([CH3:21])O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:24][O:23][C:18]([C@@H:19]([O:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH2:12][C@H:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[CH:6][CH:5]=1)=[O:3])[CH3:21])=[O:22]
Reactant: COC(=O)[C@H](C)O
Reactant: CC(C)[C@H]1COC(c2ccc(C(=O)O)cc2)=N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](C)OC(=O)c1ccc(C2=N[C@@H](C(C)C)CO2)cc1

Procedure:
(S)-2-(4-Carboxyphenyl)-4-isopropyl-2-oxazoline (2.0 g), 0.5 g of methyl (S)-lactate and 0.1 g of 4-(dimethylamino)pyridine are dissolved in 50 ml of dichloromethane and the solution is treated portionwise with 1.4 g of N,N'-dicyclohexylcarbodiimide within 10 minutes while stirring. The mixture is stirred at room temperature overnight and then filtered. The filtrate is diluted with dichloromethane, washed twice with 50 ml of saturated sodium carbonate solution each time and then with water, dried over magnesium sulphate and concentrated. The crude product obtained is purified by chromatography on silica gel with toluene. The (S)-2-[4-([(S)-1-(methoxycarbonyl)-1-ethoxy]carbonyl)phenyl]-4-isopropyl-2-oxazoline obtained is recrystallized from ethanol;
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:16]=1)(=[O:12])=[O:11]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Cl)c(Cl)c1Cl
Yield: 64.3 %

Procedure:
A solution of 2,3,4-trichlorobenzenesulfonyl chloride (15 mg, 0.055 mmol), 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) and dry pyridine (12 μL) in CH2Cl2 (200 μL) was stirred at room temperature over night. The solvent was evaporated and the crude product was purified by preparative HPLC (ACE C8, 5 μm 21×50 mm, flow 25 ml/min, 50 mM NH4OAc in water/CH3CN) to give 13 mg (65%) of the title compound. MS (ESI+) calcd for C13H8Cl3N5O2S 402.946428, found 402.946188.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]([C:19](=[O:38])[CH2:20][C:21]1[NH:26][C:25]2[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:24]=2[S:23](=[O:37])(=[O:36])[N:22]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[OH:3][C:4]1[C@H:6]2[C@H:7]([CH2:8][CH2:9][CH2:10]2)[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:19](=[O:38])[C:20]=1[C:21]1[NH:26][C:25]2[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][C:24]=2[S:23](=[O:37])(=[O:36])[N:22]=1
Reactant: CCOC(=O)C1CCCC1N(Cc1ccccn1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3ccccn3)C1=O)N2
Temperature: 60 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
A solution of 2-{[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-pyridin-2-ylmethyl-amino}-cyclopentanecarboxylic acid ethyl ester (0.043 g, 0.076 mmol) in ethanol (5 mL) was treated with a 21% w/w solution of sodium ethoxide in ethanol (0.114 mL) and stirred for 16 h at 60° C. Glacial acetic acid (0.100 mL) was added, the solvents were removed in vacuo, and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-[3-(4-hydroxy-2-oxo-1-pyridin-2-ylmethyl-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (8.7 mg, 0.017 mmol, 22.4%), as a pale brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.47-1.71 (3H, m), 1.99-2.15 (3H, m), 3.06 (3H, s), 3.97-4.03 (1H, m), 4.61-4.65 (1H, m), 4.99 (1H, d, J=15.3 Hz), 7.32-7.35 (1H, m), 7.42 (1H, d, J=7.8 Hz), 7.49-7.52 (1H, m), 7.56-7.58 (2H, m), 7.80-7.84 (1H, m), 8.54 (1H, d, J=4.7 Hz), 10.18 (1H, s). LC-MS (ESI) calcd for C22H23N5O6S2 517.11, found 518.1 [M+H+].
Reaction SMILES: [O-]CC.[Na+].Cl.Cl.[NH:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH2:8].[C:15](OCC)(=[O:23])/[CH:16]=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[O:23]=[C:15]1[NH:8][N:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16]1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: NNc1cccnc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)C1CC(=O)NN1c1cccnc1
Temperature: 20 °C

Procedure:
A 4-neck round bottomed flask (250 mL) was charged with sodium ethoxide (21 wt % in ethanol, 56 mL, 192 mmol). 3-Hydrazinopyridine.dihydrochloride (10.0 g, 55.0 mmol) was added, causing an exotherm from 20° C. to 32° C. The reaction was allowed to cool to 20° C. and diethyl maleate (13.4 mL, 82.0 mmol) was added, and the reaction was heated at 60° C. for 3 hours. The reaction was cooled to 20° C. and quenched with acetic acid. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were concentrated to dryness and the residue was purified by flash column chromatography using ethyl acetate as eluent to the title compound as a blue oil (6.60 g, 51%): 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.40-8.26 (m, 1H), 8.19 (dd, J=4.4, 1.6 Hz, 1H), 7.47-7.21 (m, 2H), 4.77 (dd, J=9.8, 2.1 Hz, 1H), 4.22 (qd, J=7.1, 1.7 Hz, 2H), 3.05 (dd, J=17.0, 9.8 Hz, 1H), 1.99 (s, 1H), 1.25 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 170.37, 146.60, 142.60, 137.28, 123.54, 121.94, 65.49, 61.32, 32.15, 20.72, 13.94; ESIMS m/z 236 ([M+H]+).