Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl[C:11]1[C:16](=O)C(Cl)=C(Cl)[C:13](=O)[C:12]=1Cl.Cl.C(=O)/C=C/C>CC(O)CC>[CH3:13][C:12]1[CH:11]=[CH:16][C:6]2[C:4](=[CH:3][C:2]([F:1])=[C:8]([F:9])[CH:7]=2)[N:5]=1
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: C/C=C/C=O
Agent: Cl
Solvent: CCC(C)O
Product: Cc1ccc2cc(F)c(F)cc2n1
Temperature: 50 °C

Procedure:
To a refluxing solution of 3,4-difluoroaniline (2.30 ml, 23.2 mmoles), tetrachloro-1,4-benzoquinone (5.70 g, 23.2 mmoles), and concentrated hydrochloric acid (6 ml) in 2-butanol (40 ml) is added crotonaldehyde (1.92 ml, 23.2 mmoles). After 2.5 hours the reaction mixture is concentrated and the resulting residue is stirred in warm (50° C.) THF (15 ml). This mixture is cooled (0° C.) and the solid collected by filtration and washed with cold THF. The solid is stirred in distilled water (200 ml), and the resulting solution made basic with K2CO3 and extracted with EtOAc (3×100 ml). The organic extracts are combined and dried over sodium sulfate, and then concentrated to give the title compound. MS (ESI) 180 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@@H:5]([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([N:31]2[CH2:35][CH2:34][C@@H:33]([NH:36][C:37]([NH:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:38])[CH2:32]2)=[N:11][C:12]=3[NH:16][CH2:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:4]([OH:46])[C@@H:3]1[OH:47].O=C1CCC(=O)N1[O:55][C:56](=O)[CH2:57][NH:58]C(OC(C)(C)C)=O.[ClH:67]>C1COCC1.CCO>[ClH:67].[ClH:67].[NH2:58][CH2:57][C:56]([NH:1][C@H:2]1[CH2:6][C@@H:5]([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([N:31]2[CH2:35][CH2:34][C@@H:33]([NH:36][C:37]([NH:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:38])[CH2:32]2)=[N:11][C:12]=3[NH:16][CH2:17][CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:4]([OH:46])[C@@H:3]1[OH:47])=[O:55]
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: NCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-{(R)-1-[9-((1R,2S,3R,4S)-4-amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-3-pyridin-3-yl-urea (Example 26 step 2) (17 mg, 26 μmol) in THF (1 ml) is treated with tert-butoxycarbonylamino-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (9 mg, 29 μmol) and stirred at room temperature overnight. The resulting solution is treated with 1.25 M HCl in EtOH (1 ml) and stirred at room temperature for 2 days. Purification by C-18 reverse phase column chromatography eluting with acetonitrile:water:HCl (0.1%) (gradient of 0 to 100% acetonitrile) yields the title compound. (MH+ 691.99)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)(Cl)Cl)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[OH:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24]([C:23]1[CH:29]=[CH:30][C:31]2[O:32][C:9]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[O:20][C:21]=2[CH:22]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: Clc1cc(Cl)cc(C(Cl)(Cl)c2cc(Cl)cc(Cl)c2)c1
Product: CCOC(=O)c1ccc2c(c1)OC(c1cc(Cl)cc(Cl)c1)(c1cc(Cl)cc(Cl)c1)O2

Procedure:
This compound was prepared from bis-(3,5-dichlorophenyl)dichloromethane and ethyl 3,4-dihydroxybenzoate according to Example 269d; light red solid, m.p.: 89° C.; MS: m/e=484 ([M]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18])[CH2:6]2.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH:23]=O>C(O)C.O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH:18][CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])[CH2:6]2
Reactant: COC(C=O)OC
Reactant: COc1cc2c(cc1OC)[C@@H](CN(C)CCCN)C2
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OC)[C@@H](CN(C)CCCNCC(OC)OC)C2
Reaction time: 12 h
Yield: 90 %

Procedure:
1 g (3.7 mmoles) of N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N-methylpropane-1,3-diamine is dissolved in 20 mL of ethanol. 520 mg (0.45 mL) of a 60% solution of glyoxal 1,1-dimethyl acetal in water and then 100 mg of Pd/C 10% are added. The reaction mixture is hydrogenated at atmospheric pressure and ambient temperature for 12 hours. The catalyst is filtered off and the filtrate is evaporated to dryness. 1.2 g of expected product are obtained in the form of an oil.
Reaction SMILES: [CH2:1]([C:4]1[C:11]([F:12])=[C:10]([F:13])[C:7]([CH2:8][OH:9])=[C:6]([F:14])[C:5]=1[F:15])[C:2]#[CH:3].[C:16]([C:18]([CH3:28])=[CH:19][C@@H:20]1[C@@H:22]([C:23](O)=[O:24])[C:21]1([CH3:27])[CH3:26])#[N:17]>CN(C)C1C=CN=CC=1.ClCCl>[C:16]([C:18]([CH3:28])=[CH:19][C@@H:20]1[C@@H:22]([C:23]([O:9][CH2:8][C:7]2[C:6]([F:14])=[C:5]([F:15])[C:4]([CH2:1][C:2]#[CH:3])=[C:11]([F:12])[C:10]=2[F:13])=[O:24])[C:21]1([CH3:27])[CH3:26])#[N:17]
Reactant: C#CCc1c(F)c(F)c(CO)c(F)c1F
Reactant: CC(C#N)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=C(C)C#N)C2(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
Under nitrogen atmosphere, to a mixture of 0.20 g of 4-propargyl-2,3,5,6-tetrafluorobenzyl alcohol, 0.17 g of (1R)-trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid, 0.022 g of 4-dimethylaminopyridine in 7 ml of dichloromethane was added 0.21 g of N,N-dicyclohexylcarbodiimide, and the mixture was stirred at room temperature for three hours. Then, the reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography to obtain 0.26 g of 4-propargyl-2,3,5,6-tetrafluorobenzyl (1R)-trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (hereinafter, referred to as the present compound (A)) represented by the formula (A):
Reaction SMILES: [C:1](OC)(=O)[CH2:2][SH:3].[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12](F)[C:9]=1C=O.BrC1C2C=CSC=2C=CC=1>>[F:7][C:8]1[C:9]2[CH:12]=[CH:13][S:3][C:2]=2[CH:1]=[CH:14][CH:15]=1
Reactant: COC(=O)CS
Reactant: O=Cc1c(F)cccc1F
Agent: Brc1cccc2sccc12
Product: Fc1cccc2sccc12

Procedure:
4-Fluorobenzo[b]thiophene was prepared starting from methyl thioglycolate and 2,6-difluorobenzaldehyde and then following a similar procedure to that given for 4-bromobenzo[b]thiophene in Example 9.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>CS(C)=O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:26][CH:23]2[CH2:25][CH2:24]2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: NC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Product: Clc1cc(NC2CC2)c2nccn2n1
Temperature: 100 °C
Yield: 80 %

Procedure:
To a solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.00 g, 3.21 mmol, 1.0 equiv) and p-TSA (611 mg, 3.21 mmol, 1.0 equiv) in DMSO (10.0 mL) was added cyclopropylamine (1.13 mL, 16.1 mmol, 5.0 equiv) and heated to 100° C. for 24 h. Purification by column chromatography using 50% ethyl acetate in hexanes elution gave 536 mg of the white solid, 80%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12](F)=[CH:13][C:14]=3[O:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:9]=2)[CH:5]=[C:4]([CH3:28])[N:3]=1.[CH3:29][O-:30].[Na+].CO.O>CN(C=O)C.C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:30][CH3:29])=[CH:13][C:14]=3[O:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:9]=2)[CH:5]=[C:4]([CH3:28])[N:3]=1
Reactant: Cc1cc(-c2nc3cc(F)cc(OCCN4CCCC4)c3c(=O)[nH]2)cc(C)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OCCN2CCCC2)c2c(=O)[nH]c(-c3cc(C)nc(C)c3)nc2c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-(2-pyrrolidin-1-yl-ethoxy)-3H-quinazolin-4-one (0.30 g, 0.80 mmol) in anhydrous DMF (5 mL) was added a solution of sodium methoxide in methanol (25 wt %, 0.43 g, 8.00 mmol) and the reaction mixture was stirred at 70° C. for 16 h. After cooling to room temperature, water (10 mL) was added, and the mixture was neutralized to pH approximately 6 with acetic acid. The solvent was evaporated, and the residue was purified by the Simpliflash system (2% methanol in CH2Cl2 and then 4% 7.0 M ammonia in methanol and CH2Cl2 as eluent) to give the title compound as a yellow solid. Yield: 0.100 g (32%). MP 190-191° C. 1H NMR (400 MHz, CDCl3): δ 7.59 (s, 2H), 6.86 (d, J=1.95 Hz, 1H), 6.53 (d, J=1.95 Hz, 1H), 4.25 (t, J=6.05 Hz, 2H), 3.93 (s, 3H), 3.03 (t, J=6.24 Hz, 2H), 2.69 (br s, 4H), 2.64 (s, 6H), 1.93-1.70 (m, 4H). MS (ES+) m/z: 395.22 (M+1) and 298.12 (100%).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=O)[CH2:17]CCCCCCC>>[C:1]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][C:10]1=[O:15])(=[O:8])[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:16][CH3:17]
Reactant: O=C1COCCN1C(=O)c1ccccc1
Reactant: CCCCCCCCC(=O)Cl
Product: CCCCCCCCC(=O)N1CCOCC1=O

Procedure:
Synthesized as for N-benzoyl-3-oxomorpholine (Example I) using nonanoyl chloride (Aldrich) in place of benzoyl chloride.
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[SH:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:5][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:12][CH2:13][CH2:14][OH:15])[CH:8]=[CH:7][CH:6]=1
Reactant: OCCS
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cccc(SCCO)c1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
3-Chloro-2-nitro-aniline (1.12 g, 6.5 mmol), 2-mercaptoethanol (0.60 ml, 8.6 mmol), and potassium carbonate (0.99 g, 7.1 mmol) were combined in dry DMF (15 ml) and stirred at 130° C. for 4 h. The solution was allowed to cool and was concentrated in vacuo. Purification by silica gel chromatography (70% EtOAc/hexanes) gave 1.29 g (93%) of 2-(3-amino-2-nitro-phenylsulfanyl)-ethanol as a bright red solid. 1H NMR (300 MHz, DMSO-d6) δ 7.20 (t, 1H, J=8.1 Hz), 6.80 (s, 2H), 6.73 (dd, 1H, J=8.4, 0.9 Hz), 6.63 (dd, 1H, J=7.8, 1.2 Hz), 4.92 (t, 1H, J=6.0 Hz), 3.58 (q, 2H, J=6.0 Hz), 2.98 (t, 2H, J=6.0 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:26])[N:9]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:10](=[O:13])[C:11]=1[CH3:12].[I-:27].[Na+]>C(C(C)=O)C.C(OCC)(=O)C>[I:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:26])[N:9]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:10](=[O:13])[C:11]=1[CH3:12]
Reactant: CC1=C(CCCCCCl)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CC1=C(CCCCCI)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 80 °C
Reaction time: 19 h
Yield: 77.9 %

Procedure:
A mixture of 11.68 g of 4-[3-(5-chloropentyl)-2,5-dihydro-4-methyl-2,5-dioxo-1H-pyrrol-1-yl]-2-(trifluoromethyl)benzonitrile and 18.2 g of sodium iodide in 180 ml of ethylmethylketone was stirred under a nitrogen atmosphere for 19 hours at 80° C. After cooling, it was diluted with ethyl acetate and washed with water as well as saturated sodium chloride solution. After drying on sodium sulfate and concentration by evaporation, 11.26 g of the title compound was obtained as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH:31][C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[O:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccc2nc3ccsc3c(=O)n2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1ccc2nc3ccsc3c(=O)n2c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (1.0 g, 0.0041 mol) and 1,1'-carbonyldiimidazole (1.35 g, 0.0082 mol) in dimethylformamide (10 ml) is heated at 95°-100° C. with stirring under nitrogen for 1.5 hours. 5-Aminotetrazole monohydrate (0.42 g, 0.0041 mol) is added and the resulting mixture is heated at 100° C. for 1-5 hours. The precipitate is filtered off, washed with tetrahydrofuran and recrystallized from dimethylformamide to give the product (0.6 g.), mp 295°-296° C.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4]>O>[CH2:3]([C:2](=[CH:1][CH2:2][CH2:3][CH3:4])[CH:1]=[O:5])[CH3:4]
Reactant: CCCC=O
Solvent: O
Product: CCCC=C(C=O)CC

Procedure:
The aldol reaction of n-butyraldehyde with simultaneous elimination of water to form 2-ethylhexenal is carried out worldwide on a large scale since the hydrogenation product, viz. 2-ethylhexanol, is used in large quantities as plasticizer alcohol. As catalyst, use is usually made of a base dissolved in water. The use of aqueous sodium hydroxide having an NaOH content in the percentage range is typical. The reaction is frequently carried out in a temperature range of 80-150° C., a pressure of less than 5 bar and a phase ratio of organic phase to aqueous catalyst phase of from 1 to 20 (Hydrocarbon Processing, October 1980, Section 2, pages 93-102). This reaction can, for example, be carried out in a stirred vessel (DE 19 06 850, DE 927 626), in a packed column which is operated in countercurrent (G. Dümbgen, D. Neubauer, Chemie-Ing.-Techn., 41, 974 (1969)), or in a flow tube (GB 761 203). All these processes give 2-ethylhexenal in a selectivity of up to 98% at conversions of 98.5%. A disadvantage is that at relatively high temperatures, part of the n-butyraldehyde used is irreversibly lost as a result of the Cannizzaro reaction. The butyric acid formed in the Cannizzaro reaction neutralizes the basic catalyst. Part of the catalyst solution containing a high burden of organic material therefore has to be continually discharged and replaced by fresh catalyst.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=3)[CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:22][NH2:23]>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:23][CH3:22])=[CH:16][CH:15]=3)[CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CN
Reactant: Nc1ncc(Br)nc1-c1cc(-c2ccc(CCl)cc2)no1
Solvent: CCO
Product: CNCc1ccc(-c2cc(-c3nc(Br)cnc3N)on2)cc1
Temperature: 70 °C

Procedure:
Trifluoroacetic Acid (2.500 mL) was added to a solution of tert-butyl N-[5-bromo-3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (500 mg, 0.8836 mmol) in dichloromethane (20.00 mL) and the mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was concentrated in vacuo to give 5-bromo-3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]pyrazin-2-amine (323.1 mg, assumed 100% yield) which was used as such in next step. LC/MS m/z 365.4 [M−H]− Step 2: 5-bromo-3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]pyrazin-2-amine was dissolved in ethanol, methanamine in ethanol (2.495 g, 3.300 mL, 26.51 mmol) was added and the mixture was stirred at 70° C. in a microwave. The reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. Combined organic extract was dried (MgSO4) and concentrated in vacuo yielding 5-bromo-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine as an oil that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH3:12].Cl>CCO>[Br:1][C:2]1[C:3]([CH2:11][CH3:12])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CCc1cccc([N+](=O)[O-])c1Br
Agent: Cl
Solvent: CCO
Product: CCc1cccc(N)c1Br
Yield: 81.2 %

Procedure:
A suspension of 2-bromo-1-ethyl-3-nitrobenzene (9.2 g, 40 mmol) in EtOH (100 mL) in concentrated hydrochloric acid (0.17 mL, 2 mmol) was refluxed for 2 hours. The mixture was subsequently purified by column chromatography, eluting with petroleum ether to give the title compound as a red oil (6.5 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.03 (1H, dd, J=7.6, 8.0 Hz), 6.64-6.62 (2H, m), 2.73 (2H, q, J=7.6 Hz), 1.22 (3H, t, J=7.6 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1ccc(C(=O)Nc2ccc(OC)cc2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 52 %

Procedure:
Using the procedure described in Example 59, Part E, 2-(4-tert-butylbenzoylamino)-4-amino-N-(4-methoxyphenyl)benzamide was reacted with ethanesulfonyl chloride (0.47 mmol) to yield 127 mg (52%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:24](=[O:25])[N:22]([CH:23]=1)[CH2:21][C@@H:20](O)[CH2:19][NH:18][C:17](=[O:27])[C:16]1=[C:28]3[N:29]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1.COCCN(S(F)(F)[F:40])CCOC.C(O)C.C([O-])(O)=O.[Na+]>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:24](=[O:25])[N:22]([CH:23]=1)[CH2:21][C@H:20]([F:40])[CH2:19][NH:18][C:17](=[O:27])[C:16]1=[C:28]3[N:29]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C1NC[C@H](O)Cn2cc(F)cc(c2=O)[C@H]2CCCN2c2ccn3ncc1c3n2
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCO
Product: O=C1NC[C@@H](F)Cn2cc(F)cc(c2=O)[C@H]2CCCN2c2ccn3ncc1c3n2
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
A solution of (6R,13S)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo-[15.5.2.17,11.02,6.020,24]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione (Example 5; 10 mg, 0.0251 mmol) in a mixture solvent of DCM (0.3 mL) and 3 drops of DMSO was treated with bis(2-methoxyethyl)amino-sulfur trifluoride (7.87 μL, 0.0427 mmol) at 0° C., followed by addition of a DCM (0.1 mL) solution of ethanol (0.231 mg, 0.00502 mmol), and the mixture was stirred at ambient temperature overnight. The reaction mixture was poured into saturated NaHCO3 and extracted with DCM, then dried (Na2SO4), filtered, and concentrated. The crude material was purified by reverse phase column chromatography (Biotage SP4 system C18 12+M cartridge, acetonitrile/water 5 to 50%) to give the title product as beige solid (1.3 mg, 12% yield). MS (apci) m/z=401.2 (M+H).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14](OCC)=[O:15])=[C:10]1[C:19](OCC)=[O:20].O.[NH2:26][NH2:27].Cl>C(O)C>[C:1]1([CH3:24])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]1[C:10]2[C:19](=[O:20])[NH:26][NH:27][C:14](=[O:15])[C:11]=2[CH:12]=[CH:13]1
Reactant: NN
Reactant: CCOC(=O)c1ccn(-c2c(C)cc(C)cc2C)c1C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(-n2ccc3c(=O)[nH][nH]c(=O)c32)c(C)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
A mixture of diethyl 1-mesityl-1H-pyrrole-2,3-dicarboxylate (3.4 g, 10.3 mmol), hydrazine monohydrate (2.0 ml, 41.3 mmol) and ethanol (20 ml) was heated under reflux for 48 hours. The mixture was acidified by addition of 5N hydrochloric acid and stirred at 80° C. for 20 min. After cooling, the crystals were collected by filtration to give 2.60 g (94%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([OH:17])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][OH:24]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([O:17][CH2:22][CH2:23][OH:24])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(O)C2=O
Reactant: OCCBr
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(OCCO)C2=O

Procedure:
Employing 8-tert-butyloxycarbonyl-2-hydroxy-2,8-diazaspiro[4,5]decane-1,3-dione (0.56 g) and 2-bromoethanol (210 μl), reaction was conducted in the same manner as in Example 40 to obtain 0.40 g of a coloress solid, m.p. 97° to 98° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Cl:17][CH2:18][CH:19]([OH:22])[CH2:20]O.O.CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[O:22][CH:19]([CH2:18][Cl:17])[CH2:20][O:9]2)=[CH:4][CH:3]=1
Reactant: OCC(O)CCl
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(C2(c3ccc(F)cc3)OCC(CCl)O2)cc1
Yield: 100 %

Procedure:
A mixture of 10 parts of bis(4-fluorophenyl)methanone, 22.1 parts of 3-chloro-1,2-propanediol, 0.2 parts of 4-methylbenzenesulfonic acid hydrate and 90 parts of methylbenzene was stirred and refluxed for 23 hours using a water-separator. The reaction mixture was poured onto alkaline water. Upon stirring, the layers were separated. The organic phase was washed with alkaline water, dried, filtered and evaporated, yielding 14 parts (100%) of 2,2-bis(4-fluorophenyl)-4-(chloromethyl)-1,3-dioxolane as a residue (intermediate 99).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10](=[O:12])[NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([Cl:13])[CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1cccc(Cl)c1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(Cl)c1
Reaction time: 5 h
Yield: 86.3 %

Procedure:
To a solution of N-tert-butoxycarbonyl glycine (0.5 g, 2.85 mmol) in dichloromethane (25 ml) at rt was added 3-chloroaniline (0.43 g, 3.42 mmol), HOBt (0.58 g, 4.28 mmol), EDC (1.10 g, 5.7 mmol) and N-methyl morpholine (0.43 g, 4.28 mmol). The reaction was stirred for 5 h and then washed with 1M KHSO4, 10% NaHCO3 solution and brine. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give [(3-chloro-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (0.7 g, 86%). HPLC-MS 284, 286 [M+1]+.