Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1](=[S:5])([OH:4])([OH:3])[SH:2].[OH-].[Ca+2:7].[OH-].C(OCCOCCOCCO)CCC.OO>O>[P:1]([O-:4])([O-:3])([S-:5])=[S:2].[Ca+2:7].[P:1]([O-:4])([O-:3])([S-:5])=[S:2].[Ca+2:7].[Ca+2:7]
Reactant: OP(O)(=S)S
Agent: OO
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCCCOCCOCCOCCO
Solvent: O
Product: [O-]P([O-])(=S)[S-]
Temperature: 42 °C

Procedure:
To a three neck flask were added 102.1 grams of the dithiophosphoric acid obtained from Example 9 and 10.6 grams of calcium hydroxide. The reaction was heated to 42° C. The temperature then increased rapidly to 115° C. The reaction was placed in a water bath and the temperature decreased back to 30° C. This gave a viscous product, to which 20.3 grams of triethylene glycol monobutyl ether were added. The reaction was then heated back to 98° C., and was then stopped heating. After cooling back to 37° C., 4.4 grams of 35% hydrogen peroxide were added over a period of one and one half hours. The reaction was then heated back to 119° C. under vacuum and water was removed by distillation. The product was then filtered with diatomaceous earth.
Reaction SMILES: [CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6][C:5](=S)[N:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15].C(Cl)Cl.[BH4-].C([O+](CC)CC)C.Cl.[CH3:34][O:35][NH2:36]>CO.C(N(CC)CC)C>[CH3:34][O:35][N:36]=[C:5]1[N:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:15])[C:2]([CH3:1])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1
Reactant: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=O
Reactant: CON
Agent: CC[O+](CC)CC
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CON=C1SC(C)(c2ccccc2)C(=O)N1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
5-Methyl-5-phenyl-3-phenylamino-2-thioxothiazolidin-4-one (0.87 g) was mixed with a 1M methylene chloride solution of triethyloxonium tetrahydroborate (3 ml) at room temperature. The reaction mixture was stirred overnight at room temperature. Methoxyamine hydrochloride (0.25 g) and triethylamine (0.61 g) in methanol (10 ml) were then added at room temperature to the mixture. After 1 hr. the solvents were evaporated under reduced pressure. The residue was purified by column chromatography (chloroform) to yield 2-methoxyimino-5-methyl-5-phenyl-3-phenylaminothiazolidin-4-one (0.38 g) having a melting point of 133-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C:14]([O:16]C2C=CC=CC=2)=O)[CH:3]=1.[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=2)[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([S:38]([NH:41][C:14]([NH:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:12]=[CH:11][C:5]=3[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:16])(=[O:40])=[O:39])=[CH:36][CH:37]=2)[CH2:25][CH2:24]1
Reactant: NS(=O)(=O)c1ccc(OCCN2CCOCC2)cc1
Reactant: CCOC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: CCOC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(OCCN2CCOCC2)cc1

Procedure:
As the starting substances, ethyl 4-chloro-2-phenoxycarbonylaminobenzoate and 4-(2-morpholinoethyloxy)benzenesulfonamide were used and the same method was applied as in Example 36 to obtain N-[4-(2-morpholinoethyloxy)benzenesulfonyl]-N'-(2-ethyloxycarbonyl-5-chlorophenyl)urea and further to obtain from 500 mg (0.98 mmol) of N-[4-(2-morpholinoethyloxy)benzenesulfonyl)-N'-(2-carboxyl-5-chlorophenyl)urea 120 mg of the above-identified compound (yield 27.2%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6):2.48 (4H,t), 2.73 (2H,t), 3.57 (4H,t), 4.22 (2H,t), 7.12 (1H,s), 7.20 (3H,t), 7.85 (1H,d), 8.09 (2H,d), 11.56 (1H,br).
Reaction SMILES: Br[C:2]1[N:3]([CH3:10])[C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.Cl.[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:21].CCOC(C)=O>CN1CCCC1=O>[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:3]([CH3:10])[C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=2)[CH2:25][CH2:24]1)=[O:21]
Reactant: Cn1c([N+](=O)[O-])cnc1Br
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc([N+](=O)[O-])n3C)CC2)c(Cl)c1Cl

Procedure:
TEA (0.26 ml, 1.86 mmol) was added to a mixture of 2-bromo-1-methyl-5-nitro-1H-imidazole (G. B. Barlin, J. Chem. Soc. B, 1967, 641; 126 mg, 0.61 mmol,) and 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1), 191 mg, 0.61 mmol) in 1-methyl-2-pyrrolidinone (1.5 ml). Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 30 min. EtOAc was added and the solution was washed with water (2×). The organic phase was separated, dried over MgSO4, and concentrated under vacuum. The crude material was purified by chromatography on silica gel using 50% EtOAc/hexanes to give 158 mg of the title product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1nc2ccccc2o1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2oc(N3CCNCC3)nc2c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
In 200 ml of acetonitrile were dissolved 33.6 g (0.39 mole) of piperazine and 10.0 g (0.065 mole) of 2-chlorobenzoxazole, and 9.0 g (0.065 mole) of potassium carbonate and a catalytic amount of potassium iodide were added thereto. The mixture was refluxed by heating for 11 hours under stirring. The mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (the eluent used was a mixture of chloroform : methanol = 9 : 1) to obtain 7.54 g of 1-(2-benzoxazolyl)piperazine as white crystals.
Reaction SMILES: C1(N2C(C(F)(F)F)=C(C3ON=C4C5C(CCC=34)=CC(C=C)=CC=5)C=N2)C=CC=CC=1.[CH:31]([C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)/[C:39](=[N:43]/[OH:44])/[CH2:38][CH2:37][CH2:36]2)=[CH2:32].[C:45]([C:47]1[C:48]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[N:49][S:50][C:51]=1[C:52](OC)=O)#[N:46]>>[C:56]1([C:48]2[C:47]([C:45]#[N:46])=[C:51]([C:52]3[O:44][N:43]=[C:39]4[C:40]5[C:35]([CH2:36][CH2:37][C:38]=34)=[CH:34][C:33]([CH:31]=[CH2:32])=[CH:42][CH:41]=5)[S:50][N:49]=2)[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: COC(=O)c1snc(-c2ccccc2)c1C#N
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Agent: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1snc(-c2ccccc2)c1C#N

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 89A employing 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1) and methyl 4-cyano-3-phenylisothiazole-5-carboxylate (Preparation 106A) as starting materials. The compound had an HPLC retention time=4.30 min. (condition C); LC/MS M+1=424.9.
Reaction SMILES: [CH2:1]([Br:4])[C:2]#[CH:3].[Na].[CH:6](=[N:13][OH:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[Br:4][CH2:1][C:2]1[O:14][N:13]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1
Reactant: C#CCBr
Reactant: ON=Cc1ccccc1
Agent: [Na]
Solvent: ClCCl
Product: BrCc1cc(-c2ccccc2)no1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a solution of propargyl bromide (1.51 ml, 20 mmol) in dichloromethane (15 ml) and aqueous sodium hyopchlorite (22.4 ml, 10%, 30 mmol) at 0° C. was added dropwise with stirring benzaldoxime (2.42 g, 20 mmol) in dichloromethane (15 ml). When addition was complete the ice bath was removed and the reaction stirred for a further 2 h. The organic layer was separated and the aqueous layer washed with dichloromethane (2×20 ml) then the combined organic layers dried (MgSO4). Solvent removal under reduced pressure gave a solid which was recrystallised from 40°-60° C. petroleum ether fraction to give the desired isoxazole (2.64 g, 11.1 mmol, 55%); mp 82°-3° C., δH (CDCl3) 4.40(2H, s, CH2 -Br), 6.50(1H, s, CH-4), 7.3-7.9(5H, m, C6H5).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][CH2:10][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].[F:28][C:29]1[CH:30]=[CH:31][C:32]([O:39][CH3:40])=[C:33]([C:35](=[N:37]O)[NH2:36])[CH:34]=1.CCN(C(C)C)C(C)C>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([O:39][CH3:40])=[C:33]([C:35]2[N:36]=[C:16]([C:15]3[CH:19]=[CH:20][C:12]([N:11]([CH2:10][CH2:9][O:8][CH3:7])[CH2:24][CH2:25][O:26][CH3:27])=[C:13]([N+:21]([O-:23])=[O:22])[CH:14]=3)[O:18][N:37]=2)[CH:34]=1
Reactant: COCCN(CCOC)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(CCOC)c1ccc(-c2nc(-c3cc(F)ccc3OC)no2)cc1[N+](=O)[O-]

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 31 (149 mg; 0.5 mmol; 1 eq.), Intermediate 23 (92 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 50/50) followed by crystallisation from Et2O/n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20]O)=[CH:16][N:15]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[CH2:43]([NH:47][CH2:48][CH:49]([CH3:51])[CH3:50])[CH:44]([CH3:46])[CH3:45]>C(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20][N:47]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:16][N:15]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCO)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Reactant: CC(C)CNCC(C)C
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2cc(C#CCN(CC(C)C)CC(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Reaction time: 72 h

Procedure:
A solution of N-[4-chloro-5-(3-hydroxy-prop-1-ynyl)-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (9.0 g, 19.7 mmol) and Et3N (2 mL) in DCM (50 mL) was treated with MsCl (15.3 mL, 19.7 mmol) at 0° C. for 20 min and evaporated to give a yellow solid, containg mostly the desired mesylate (10.7 g). An aliquot of this solid (106.8 mg, 0.2 mmol) was treated with diisobutylamine (25.9 mg, 24.8 μL) in DCM (2 mL) at 0° C. for 10 h, and then at 25° C. for 3 days. Evaporation and prepartive plate chromatography gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[C:11]([CH3:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:27])[C:12]([CH2:16][C:17]([OH:19])=[O:18])=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1CC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(OCc2ccccc2)cc(C)c1CC(=O)O
Yield: 80 %

Procedure:
0.35 g of benzyl 2-(4-benzyloxy-2,6-dimethylphenyl)acetate was shaken overnight with a mixture of 7 ml of methanol, 0.7 ml of water and 0.28 g of solid sodium hydroxide. The resulting solution was evaporated and the residue was partitioned between 50 ml of methylene chloride and 25 ml of 2M hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and evaporated. The solid residue was recrystallized from a mixture of 3 ml of methanol and 3 ml of water to give 0.21 g of 2-(4-benzyloxy-2,6-dimethylphenyl)acetic acid of melting point 149°-150° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C:5]=2[N:6]=1>FC(F)(F)C(O)=O.ClCCl>[CH3:1][C:2]1[O:3][C:4]2[CH2:9][NH:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2c(o1)CN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2c(o1)CNC2

Procedure:
tert-Butyl 2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d][1,3]oxazole-5-carboxylate (110 mg) obtained in Step C was dissolved in a mixture of trifluoroacetic acid and dichloromethane (2 mL, 1:1) and evaporated under reduced pressure after one h. The residue was then purified on a Biotage Horizon® system (silica, 4% methanol, 0.4% saturated ammonium hydroxide, 95.6% dichloromethane) to yield the title compound. LC-MS 125.2 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22]1[C:23]2[C:28]([CH:29]=[C:30]3[C:35]=1[CH:34]=[CH:33][CH:32]=[CH:31]3)=[CH:27][CH:26]=[CH:25][CH:24]=2>>[CH:24]1[C:23]2[C:28](=[CH:29][C:30]3[C:35]([C:22]=2[CH2:21][N:7]2[C:8]([O:9][C:10]4[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=4)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2c3ccccc3cc3ccccc23)c(=O)[nH]c1=O
Yield: 41.5 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 9-chloromethyl anthracene were reacted by the same way with the example 1 to obtain the titled compound (187 mg, yield: 41.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([C:22]([OH:24])=[O:23])=[CH:8][CH:9]=1.[C:25]([N:32]1[CH2:36][CH2:35][CH:34](O)[CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:28]([O:27][C:25]([N:32]1[CH2:36][CH2:35][CH:34]([O:23][C:22]([C:7]2[CH:6]=[C:5]3[C:10]([S:11](=[O:21])(=[O:20])[NH:12][C:13]4[C:4]3=[CH:3][C:2]([Cl:1])=[C:19]3[C:14]=4[N:15]=[CH:16][CH:17]=[CH:18]3)=[CH:9][CH:8]=2)=[O:24])[CH2:33]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)c2ccc3c(c2)-c2cc(Cl)c4cccnc4c2NS3(=O)=O)C1
Yield: 48.9 %

Procedure:
In a similar fashion using route 54 general procedure 123, 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 524 (100 mg, 0.27 mmol), 1-Boc-3-pyrrolidinol (0.11 g, 0.55 mmol), EDC.HCl (80 mg, 0.41 mmol), HOBt (56 mg, 0.41 mmol) and DMF (1 ml) gave the title compound (70 mg, 47%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C=O.C[C:21]([O-:24])(C)C.[K+]>CS(C)=O>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:21][OH:24])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: C=O
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 665.1 %

Procedure:
A solution of 4-methyl-3-nitro-benzoic acid tert-butyl ester (8.66 g, 36.5 mmol) in anhydrous DMSO (135 mL) was treated with paraformaldehyde (1.32 g, 44.0 mmol, 1.2 eq.) followed by t-BuOK (0.32 g, 2.7 mmol, 0.074 eq.). The mixture was stirred at room temperature for 2.5 h and quenched with aqueous NH4Cl (250 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine and water, and then dried (Na2SO4) and concentrated. Silica gel chromatography using ethyl acetate (0→30%) in dichloromethane provided 4-(2-hydroxy-ethyl)-3-nitro-benzoic acid tert-butyl ester (4.8 g, white solid): 1H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H), 8.13 (dd, 1H), 7.49 (d, 1H), 3.96 (q, 2H), 3.20 (t, 2H), 1.60 (s, 9H), and 4-(2-hydroxy-1-hydoxymethyl-ethyl)-3-nitro-benzoic acid tert-butyl ester (3.7 g, white solid): 1H NMR (400 MHz, CDCl3) δ 8.35 (d, 1H), 8.15 (dd, 1H), 7.65 (d, 1H), 4.05 (t, 4H), 3.61 (Q, 1H), 2.05 (t, 2H), 1.59 (s, 9H).
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[NH2:28][OH:29]>C(O)C>[F:1][CH:2]([F:27])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([CH:25]=[N:28][OH:29])[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: O=Cc1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Reactant: NO
Solvent: CCO
Product: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C=NO)cs2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde (2.00 g) in ethanol (33 ml) was added dropwise hydroxylamine (50% in water, 0.36 ml) at room temperature. The reaction mixture was stirred at room temperature for 24 hours, then the solvent was removed under reduced pressure. This gave 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde oxime (2.00 g).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:13])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].C(=O)(O)[O-].[Na+].C(OCC)C.[BH4-].[Na+]>O>[OH:13][CH:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: O=C([O-])O
Agent: O=CN=c1[nH]c(C(=O)C(=O)O)cs1
Agent: [BH4-]
Solvent: O
Solvent: CCOCC
Product: O=CNc1nc(C(O)C(=O)O)cs1
Reaction time: 8 h

Procedure:
To a suspension of 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, (20 g.) in water (400 ml.) was added sodium bicarbonate (8.4 g.) under ice-cooling and stirring, and the mixture was stirred for 10 minutes at the same temperature, and then diethyl ether (10 ml.) was added thereto. To the mixture was added sodium borohydride (1.52 g.) over 10 minutes with stirring at the same temperature, and the mixture was stirred for 1 hour and 50 minutes at the same temperature. After the reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 4.0 with 10% hydrochloric acid and then concentrated under reduced pressure till the volume became 100 ml. The concentrated filtrate was adjusted to pH 1 with 10% hydrochloric acid, and crystallization was induced by scratching. The concentrated filtrate was stirred for 1 hour at room temperature and then allowed to stand overnight in a refrigerator. The precipitates were collected by filtration, washed with ice-water twice and then dried under suction to give 2-hydroxy-2-(2-formylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-hydroxy-2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, (14.8 g.), mp. 188° to 189° C. (dec.).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:44])[NH:11][C@H:12]([CH2:28][C:29]([NH:31][CH2:32][CH:33]([OH:43])[CH2:34][NH:35]C(OC(C)(C)C)=O)=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[CH2:2]([N:17]([CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]([NH:11][C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:44])[CH2:28][C:29]([NH:31][CH2:32][CH:33]([OH:43])[CH2:34][NH2:35])=[O:30])[C:18](=[O:19])[OH:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)C[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(O)CNC(=O)C[C@H](CCCCN(Cc1ccccc1)C(=O)O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11 ml of a 4M solution of hydrogen chloride in dioxane are added to a solution of 160 mg (0.267 mmol) of benzyl{(1S)-5-{[(benzyloxy)carbonyl]amino}-1-[2-({3-[(tert-butoxycarbonyl)amino]-2-hydroxypropyl}amino)-2-oxoethyl]pentyl}carbamate (Example 160A) in 5.5 ml of dioxane at 0° C. The mixture is stirred at RT for 1 h. The reaction solution is concentrated, coevaporated with dichloromethane several times and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].C(N(CC)CC)C.[C:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)#[CH:24].CCOC(C)=O>CN(C=O)C.[Cu]I.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>[CH:25]1([C:23]2[N:11]([S:12]([CH3:15])(=[O:14])=[O:13])[C:3]3[C:2]([CH:24]=2)=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][CH:4]=3)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C#CC1CCCCC1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1c(C2CCCCC2)cc2cc([N+](=O)[O-])ccc21
Temperature: 70 °C
Reaction time: 18 h
Yield: 91.9 %

Procedure:
To a mixture containing N-(2-iodo-4-nitrophenyl)methanesulfonamide (13.5 g; 39.5 mmol), triethylamine (17.9 ml; 129 mmol), ethynylcyclohexane (8.55 g; 79 mmol) in DMF (60 ml), CuI (1.5 g; 7.9 mmol) and dichlorobis(triphenylphosphine)palladium(II) [Cl2(PPh3)2Pd] (2.77 g; 3.95 mmol) were added. The reaction mixture was left under stirring at 70° C. for 18 hours. After cooling to room temperature, EtOAc (100 ml) was added, the inorganic precipitate was filtered off and the solution was transferred into a separating funnel and washed with NaHCO3 (saturated solution, 3×200 ml) and water (2×150 ml). The organic phase was dried over Na2SO4, the solvent was removed by evaporation under reduced pressure. The so obtained crude product was crystallized (isopropyl ether) to give 2-cyclohexyl-1-(methylsulfonyl)-5-nitro-1H-indole (11.7 g)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][C:22]([CH3:28])=[CH:23][C:24]=1[C:25](O)=[O:26])/[C:12](=[O:18])[NH:13]2.[CH3:29][NH:30][CH2:31][CH:32]([OH:39])[CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:39][CH:32]([CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:31][N:30]([CH3:29])[C:25]([C:24]1[CH:23]=[C:22]([CH3:28])[NH:21][C:20]=1/[CH:19]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH:17]=[CH:16][CH:15]=2)=[O:26]
Reactant: CNCC(O)CN1CCCC1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C(=O)N(C)CC(O)CN2CCCC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]1

Procedure:
2-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (115 mg, 0.3 mmol) was coupled with 1-methylamino-3-pyrrolidin-1-yl-propan-2-ol (3 eq.), EDC (2 eq.), HOBt (1 eq.) in DMF (1.5 mL) to give 108 mg of the titled compound as a yellow solid. MS 521.2 [M++1].