Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C@H:6]1[C@@H:9]([N:10]=[N+:11]=[N-:12])[C:8](=[O:13])[NH:7]1)(=O)=O.[Li+].[Br-:22].C(OCC)(=O)C>CN(C)C=O>[N:10]([C@H:9]1[C:8](=[O:13])[NH:7][C@H:6]1[CH2:5][Br:22])=[N+:11]=[N-:12]
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2N=[N+]=[N-])cc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@H]1C(=O)N[C@H]1CBr

Procedure:
A degassed solution of cis-3-azido-4-oxo-2-azetidinylmethyl tosylate (0.41 g, 1.4 mmol) in dimethylformamide (5 ml) was heated to 90° with LiBr (0.43 g, 5 mmol) for 4 hours. The reaction was poured into ethyl acetate and washed copiously with water. The dried solution was evaporated to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([OH:21])[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.Cl[CH2:23][C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)[N:27]=[C:26]([OH:36])[CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][CH2:23][C:24]3[CH:25]=[C:26]([OH:36])[N:27]=[C:28]([C:30]4[CH:35]=[N:34][CH:33]=[CH:32][N:31]=4)[N:29]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Reactant: Oc1cc(CCl)nc(-c2cnccn2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)c2cc(OCc3cc(O)nc(-c4cnccn4)n3)c3c(c2)OC(C)(C)C3)n1
Temperature: 60 °C
Yield: 9.8 %

Procedure:
To a solution of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (80 mg, 0.280 mmol) and 6-(chloromethyl)-2-(pyrazin-2-yl)pyrimidin-4-ol (124 mg, 0.557 mmol) in 3 mL of DMF was added Cs2CO3 (181 mg, 0.557 mmol). The mixture was heated at 60° C. overnight, then filtered, washed with EtOAc, concentrated, and purified by reverse phase HPLC to give a white solid (13 mg, 10% yield). 1H NMR (400 MHz, CDCl3) δ 9.67 (d, J=1.52 Hz, 1 H) 8.83 (d, J=2.53 Hz, 1 H) 8.65-8.67 (m, 1H) 8.50 (s, 1 H) 7.27-7.31 (m, 1 H) 7.06 (d, J=1.01 Hz, 1 H) 6.88 (s, 1 H) 6.76-6.82 (m, 1 H) 6.72 (s, 1 H) 5.13 (s, 2 H) 3.81 (s, 3 H) 3.11 (s, 2 H) 1.49-1.55 (m, 6 H); LCMS for C24H23N7O4 m/z 474.00 (M+H+).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[CH:7]([NH:10][NH2:11])([CH3:9])[CH3:8].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH:12](=[N:11][NH:10][CH:7]([CH3:9])[CH3:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)NN
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)NN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a round-bottom flask containing anhydrous sodium acetate (8.2 g, 0.1 mol) in 125 ml 50% ethanol was added isopropylhydrazine HCl salt (11.1 g, 0.1 mole) and benzaldehyde (10.6 g, 0.1 mole). The mixture was stirred at rt for 20 h. The reaction was extracted with ether (3×250 ml). The organic layers were combined and washed with aqueous sodium bicarbonate solution and brine and dried over sodium sulfate. Filtration, concentration, and co-evaporation with toluene (3×) provided the title compound as an oil. MS m/z 163.3 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[C:6]=1[NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:4].[Li+].[OH-]>O.O1CCOCC1>[C:17](/[CH:16]=[CH:15]/[C:7]1[C:6]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:5]([C:3]([OH:4])=[O:2])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)([OH:19])=[O:18]
Reactant: COC(=O)c1c2c(cc(/C=C/C(=O)O)c1NS(=O)(=O)c1ccccc1)CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1cc2c(c(C(=O)O)c1NS(=O)(=O)c1ccccc1)CCCC2
Temperature: 160 °C

Procedure:
A solution of Example 476D (20 mg, 0.05 mmol) in 0.5 mL of 2:1 dioxane water was treated with LiOH (13 mg, 0.3 mmol) and heated to 160° C. for 27.5 minutes in a microwave reactor. The reaction mixture was concentrated and the residue was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 419 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 12.92 (br s, 1H), 12.11 (br s, 1H), 9.69 (br s, 1H), 7.60 (m, 2H), 7.54 (m, 1H), 7.49-7.42 (m, 4H), 6.13 (d, 1H), 2.75 (m, 2H), 2.67 (m, 2H), 1.70 (m, 4H).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CC(C)CCO>[NH3:6].[N:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: Clc1ccncc1
Reactant: C1CNCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Product: N
Product: c1cc(N2CCCNCC2)ccn1

Procedure:
A suspension of 4-chloropyridine hydrochloride (7.5 g) in 3-methyl-1-butanol (100 ml) was added dropwise to a refluxing solution of hexahydro-1,4-diazepine (10.0 g) and triethylamine (16.8 ml) in 3-methyl-1-butanol (300 ml). After addition the solution was refluxed for 18 hours. The solvent was removed in vacuo to give an oil. Purification by sinter-column chromatography on silica gel, eluting with dichloromethane containing an increasing proportion of methanol (2-5%) and a small amount of conc. aqueous ammonia, gave 1-(4-pyridyl)hexahydro-1,4-diazepine as a colourless oil which slowly crystallised on standing.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])C)([CH3:4])([CH3:3])C.[CH:12](N)([CH3:14])[CH3:13].C(N(CC)CC)C.C(Cl)(=O)C1C=CC=CC=1>>[CH:1]([NH:5][C:6](=[O:11])[C:7]1[CH:9]=[CH:14][CH:12]=[CH:13][CH:10]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(C)NC(=O)C(C)(C)C
Reactant: CC(C)N
Solvent: CCN(CC)CC
Solvent: O=C(Cl)c1ccccc1
Product: CC(C)NC(=O)c1ccccc1
Yield: 92 %

Procedure:
In a fashion similar to the preparation of LtBu,tBuH, treatment of isopropylamine (9.0 mL, 105 mmol) and triethylamine (14.9 mL, 105 mmol) with benzoyl chloride (11.72 mL, 100 mmol) afforded LPh,iPrH as white crystalline solid (15.02 g, 92%) upon crystallization of the crude product from Et2O at −20° C. followed by sublimation at 70° C./0.05 Torr: mp 101-103° C.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O-:9])=[O:8])[CH2:2]1.[CH3:10]O>[Pd].C>[S:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1
Reactant: O=C([O-])C1=CCCSC1
Reactant: CO
Agent: [Pd]
Product: COC(=O)C1=CC=CSC1
Yield: 96 %

Procedure:
A solution of 832 mg (4.37 mmole) of 5,6-dihydro-2H-thiopyran-3-carboxylate, 1,1 dioxide from part D in methanol (40 mL) was hydrogenated in the presence of 400 mg (50% wt) of 10% Pd/charcoal for 4 hrs. at room temperature and 50 psig of H2. The catalyst was removed by vacuum filtration through a short plug of packed celite and the solvent removed in vacuo to give 802 mg (96%) of methyl 2H-thiopyran-3-carboxylate, 1,1-dioxide as a white solid; mass spectrum m/z=193 (CI,M+H) Part F: Preparation of 2H-thiopyran-3-carboxylate, 1,1-dioxide.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11](=[O:24])[N:10]([CH2:25][CH2:26][CH2:27][CH3:28])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[CH2:17]([N:12]1[C:13](=[O:16])[C:14]2[NH:15][C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:30][CH:29]=3)=[N:8][C:9]=2[N:10]([CH2:25][CH2:26][CH2:27][CH3:28])[C:11]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: CS(=O)(=O)Cl
Product: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(NS(C)(=O)=O)cc3)nc21
Yield: 35 %

Procedure:
8-(4-Amino-benzyl)-1-benzyl-3-butyl-3,7-dihydro-purine-2,6-dione was condensed with methanesulfonyl chloride under the conditions previously described to give the stated sulfonamide as a pale brown solid (35%); 1H NMR(DMSO-d6, 300 MHz) δH13.54 (s, 1H), 9.76 (s, 1H), 7.45–7.25 (m, 7H), 7.22 (d, J=8.4 Hz, 2H), 5.14 (s, 2H), 4.10 (s, 2H), 4.04 (t, J=7.1 Hz, 2H), 3.03 (s, 3H), 1.80–1.65 (m, 2H), 1.40–1.25 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); EI-HRMS m/e calculated for C24H27N5O4S (M+) 481.1784, found 481.1781.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(N)(=O)=O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of p-nitrobenzoylchloride (0.925 g, 5.0 mmol) and methanesulfonamide (0.465 g, 4.9 mmol) in dry DCM (10 mL) was cooled to 0° C. To this was added triethylamine (1.48 g, 14.7 mmol) then the mixture was allowed to warm to r.t. and stirred for 12 h. Concentration in vacuo gave the crude title compound, which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35][CH2:36][CH2:37]O)[CH3:23].C(O)(C(F)(F)F)=O.[OH-].[Na+]>O>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:37][CH2:36][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CCc1oc(-c2ccccc2)nc1CCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1oc(-c2ccccc2)nc1CCCOc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 79 %

Procedure:
Intermediate 60 was prepared as described above for the preparation of intermediate 52. From 266 mg of N-(Boc)-L-Tyrosine methyl ester and 208 mg of Intermediate 8F was prepared 360 mg of BOC-protected intermediate methyl ester (79% yield; 1H NMR (CDCl3, 300 MHz) δ8.06-8.03 (m, 2H), 7.46-7.44 (m, 3H), 7.04 (d, 2H, J=8.4), 6.85 (d, 2H, J=8.4), 4.97 (d, 1H, J=7.6), 4.57 (m, 1H), 3.99 (t, 2H, J=6.0), 3.74 (s, 3H), 3.05 (m, 2H), 2.77-2.65 (m, 4H), 2.19 (t, 2H, J=6.6), 1.45 (s, 9H), 1.24 (t, 3H, J=7.5); From 352 mg of BOC-protected ester intermediate was prepared the crude TFA salt of intermediate 60. The TFA salt was suspended into water and the pH adjusted to ˜7.0 with 10% NaOH. The resulting solids were filtered and dried to yield intermediate 60; 1H NMR (DMSO-d6, 400 MHz) δ7.88-7.85 (m, 2H), 7.48-7.43 (m, 3H), 7.11 (d, 2H, J=8.5), 6.82 (d, 2H, J=8.5), 3.92 (t, 2H, J=6.2), 3.55 (m, 1H), 3.0 (dd, 1H, J=14.3, 4.8), 2.8 (dd, 1H, J=14.3, 7.7), 2.67-2.56 (m, 4H), 2.02-1.96 (m, 2H), 1.13 (t, 3H, J=7.4); low resolution MS (ES+)m/e 392.9 (MH+); TLC Rf=0.44 (4/1, DCM/MeOH).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]([CH3:12])[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(=O)Nc2ncnc(Cl)c21
Temperature: -78 °C
Yield: 56.8 %

Procedure:
Add 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.4 g; 0.0023 mol; 1.0 equiv) in THF (15 mL) and cool to −78° C. under an argon atmosphere. Add drop-wise lithium hexamethyldisilazide (4.7 mL; 0.0047 mol; 2.0 equiv; 1 M in THF). Stir the reaction at −78° C. for 30 min. Add drop-wise methyl iodide (0.29 mL; 0.0047 mol; 2.0 equiv), allow the reaction temperature to come to −20° C. slowly and stir at −20° C. for 2 h. Quench the reaction with saturated ammonium chloride aqueous and extract with EA. Evaporate the organic layer to give the title compound (0.24 g; 41.38%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH2:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:30])=[C:25]([CH:29]=1)[C:26](O)=[O:27]>>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:18][C:26](=[O:27])[C:25]1[CH:29]=[C:21]([Br:20])[CH:22]=[CH:23][C:24]=1[NH2:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1N
Yield: 82.3 %

Procedure:
(2S)-(2-amino-5-bromo-benzoyl-amino)-3-biphenyl-4-yl-propionic acid methyl ester (1.53 g, 80%) was prepared from (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 4.1 mmol) and 5-bromo-2-amino-benzoic acid (1.23 g, 4.9 mmol) as described in procedure A.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N(CC)CC)C.[CH3:49][CH:50]([S:52](Cl)(=[O:54])=[O:53])[CH3:51]>ClCCl>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH:27][C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:52]([CH:50]([CH3:51])[CH3:49])(=[O:54])=[O:53])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:12]2[O:13][C@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[C@@H:15]([OH:19])[C@H:16]2[OH:17])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)C(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (Preparation 10) (140 mg, 0.25 mmol) and triethylamine (0.05 ml, 0.36 mmol) in anhydrous dichloromethane (1 ml) was treated with a solution of 2-propanesulphonyl chloride (40 mg, 0.28 mmol) in anhydrous dichloromethane (1 ml). The mixture was stirred at room temperature for 18 hours during which time the solvent was allowed to evaporate off freely. The residue was dissolved in ethanol (1 ml), treated with hydrochloric acid (1 M, 1 ml) and heated at 60° C. for 4 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was then purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to give a solid which was triturated with diethyl ether, diluted with pentane, filtered and dried to afford the title compound as a solid (28 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12]N(C=O)C.S(Cl)(Cl)=O>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1O
Reactant: CN(C)C=O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 4-hydroxy-3-methylbenzoic acid (10.00 g, 65.7 mmol) and DMF (100 μL) in MeOH (35 mL) was added dropwise thionyl chloride (4.8 mL, 65.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with the addition of aqueous saturated sodium bicarbonate solution (50 mL), and methanol was removed under reduced pressure. The residue was extracted with EtOAc (3×50 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to provide methyl 4-hydroxy-3-methyl-benzoate (10.53 g, 96%) as a light brown solid. ESI-MS m/z calc. 166.0. found 167.1 (M+1)+; Retention time: 1.09 minutes (3 min run).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17](C=O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:24])[N:3]1[CH2:25][CH2:26][CH3:27].CC1C([P+]([O:48]C(C)=O)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=CC=1.[O:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1>>[CH3:53][O:52][C:56](=[O:48])[CH:55]=[CH:54][C@:17]12[CH2:20][CH2:21][C@@:14]([C:7]3[NH:6][C:5]4[C:4](=[O:24])[N:3]([CH2:25][CH2:26][CH3:27])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:19][CH2:18]1)[CH2:15][CH2:16]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: CC(=O)O[P+](c1ccccc1)(c1ccccc1)c1ccccc1C
Reactant: C1CCOC1
Product: CCCn1c(=O)c2[nH]c([C@]34CC[C@@](C=CC(=O)OC)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 70 °C

Procedure:
4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde (XI, Example 87a, 1 wt) and tetrahydrofuran (16.5 vol) are mixed under nitrogen and methyl(triphenylphosphoranylidene) acetate (1.85 wt) is added. The reaction mixture is heated to 65 to 75° C. and the reaction mixture stirred at this temperature until the starting aldehyde has been consumed as determined by NMR. The mixture is cooled to 35 to 40° C. and a solution of lithium hydroxide (0.45 wt) in water (16.5 vol) is added. The mixture is heated to reflux and the mixture stirred at reflux until the hydrolysis of the ester is complete (as determined by NMR, typical reaction time 3 to 6 hours). The reaction mixture is cooled to 35 to 40° and the organic solvent removed in vacuo at 40 to 45°. Ethyl acetate (10 vol) and water (6 vol) are added to the aqueous residue and the mixture is vigorously stirred for 5 to 15 mins. The phases are separated and the aqueous phase is washed with ethyl acetate (2×10 vol). The aqueous phase is filtered. The filtrate is cooled to 0 to 5° and acidified to pH=1 with concentrated hydrochloric acid (0.90 vol). The mixture is stirred at 0 to 5° for 45 to 75 mins. The resultant slurry is filtered and the filter pad washed with water (1 vol). The solid is dried in vacuo at 45 to 55° for 16 to 24 hours to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[Cl:14][C:15]1[C:16]([O:25][C:26]2[C:31]([Cl:32])=[CH:30][C:29]([N:33]=[C:34]=[O:35])=[CH:28][C:27]=2[Cl:36])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1>>[Cl:14][C:15]1[C:16]([O:25][C:26]2[C:31]([Cl:32])=[CH:30][C:29]([NH:33][C:34]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]3[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=3[F:13])=[O:35])=[CH:28][C:27]=2[Cl:36])=[N:17][CH:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:20]=1
Reactant: O=C=Nc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Reactant: CCOC(=N)c1c(F)cccc1F
Product: CCOC(=NC(=O)Nc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1)c1c(F)cccc1F

Procedure:
In a similar manner to that described in step (e) of Example I ethyl 2,6-difluorobenzimidate is reacted with 3-chloro-5-trifluoromethyl-2-(2,6-dichloro-4-isocyanatophenoxy)pyridine to give ethyl N-[4-(3-chloro-5-trifluoromethylpyrid-2-yloxy)-3,5-dichlorophenylcarbamoyl]-2,6-difluorobenzimidate (Compound IV). The intermediate isocyanate is obtained by the procedure of step (c) of Example 1 from 2-(4-amino-2,6-dichlorophenoxy)-3-chloro-5-trifluoromethylpyridine. This compound is described in Japanese published patent application No. 79-125699 (Chemical Abstracts, vol. 92, 146618d).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.FC(F)(F)S(O[C:25]1[CH2:30][CH2:29][CH:28]([N:31]2[C@@H:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:34]([CH3:43])([CH3:42])[O:33][C:32]2=[O:44])[CH2:27][CH:26]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].CO>O1CCOCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:25]3[CH2:30][CH2:29][CH:28]([N:31]4[C@@H:35]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:34]([CH3:42])([CH3:43])[O:33][C:32]4=[O:44])[CH2:27][CH:26]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CC1(C)OC(=O)N(C2CC=C(OS(=O)(=O)C(F)(F)F)CC2)[C@H]1c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CC1(C)OC(=O)N(C2CC=C(c3cnc4[nH]ccc4c3)CC2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A mixture of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1 h-pyrrolo[2,3-b]pyridine (0.477 g, 1.955 mmol), 4-((S)-5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)cyclohex-1-en-1-yl trifluoromethanesulfonate (0.82 g, 1.955 mmol) and 2.0 M sodium carbonate (4.89 mL) in dioxane (6.52 mL) was flushed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.226 g, 0.196 mmol) was added and the mixture was stirred at 100° C. overnight. The reaction mixture was diluted with CH2Cl2 and extracted with CH2Cl2. The combined organic layers were concentrated. The material thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% 1M NH3.MeOH in CH2Cl2, to provide (4S)-3-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.76 g, 1.961 mmol, 100% yield) as light-yellow solid.
Reaction SMILES: [BrH:1].[C:2]([C:5]1[S:6][C:7]2[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=1)(=[NH:4])[NH2:3].BrBr>Br>[C:2]([C:5]1[S:6][C:7]2[C:13](=[O:14])[CH:12]([Br:1])[CH2:11][CH2:10][C:8]=2[N:9]=1)(=[NH:3])[NH2:4]
Reactant: Br
Reactant: N=C(N)c1nc2c(s1)C(=O)CCC2
Agent: BrBr
Product: N=C(N)c1nc2c(s1)C(=O)C(Br)CC2
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
2-Bromo-1,3-cyclohexadione prepared in Example 1, Route 1 (A) was reacted with amidinothiourea in the similar manner to that of Example 1, Route 1(B) to give 2-amidino-4,5-dihydrobenzothiazole-7(6H)-one hydrobromide. The hydrobromide (3.4 g) was dissolved into conc. hydrobromic acid (20 ml), and one equivalent of bromine was added dropwise at a temperature of 85° C. The mixture was stirred at a temperature of 80° C. to 90° C. for 30 minutes, cooled and filtered. The solids were neutralized with sodium carbonate to give the titled compound (3.17 g, 67%).
Reaction SMILES: [ClH:1].FC1C=C(NC(=O)CC(NC2C=CC(F)=CC=2)=O)C=CC=1OC1C2=C(C)C(OC[CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=CN2N=CN=1.[F:43][C:44]1[CH:45]=[C:46]([NH:63][C:64]([NH:66][C:67](=[O:76])[CH2:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][CH:70]=2)=[S:65])[CH:47]=[CH:48][C:49]=1[O:50][C:51]1[C:56]2=[C:57]([CH3:62])[C:58]([O:60][CH3:61])=[CH:59][N:55]2[N:54]=[CH:53][N:52]=1>C1COCC1>[ClH:1].[F:43][C:44]1[CH:45]=[C:46]([NH:63][C:64]([NH:66][C:67](=[O:76])[CH2:68][C:69]2[CH:70]=[CH:71][C:72]([F:75])=[CH:73][CH:74]=2)=[S:65])[CH:47]=[CH:48][C:49]=1[O:50][C:51]1[C:56]2=[C:57]([CH3:62])[C:58]([O:60][CH2:61][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:59][N:55]2[N:54]=[CH:53][N:52]=1
Reactant: COc1cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a solution of 3-fluoro-4-(5-methyl-6-(2-morpholinoethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (30 mg, 0.072 mmol, Compound C of Example 36) in 1 mL of THF was added 2-(4-fluorophenyl)ethanoyl isothiocyanate (19 mg, 0.1 mmol, Compound A of Example 2). The solution was allowed to stir at room temperature for 2 h and HPLC analysis indicated the completion of the reaction. The reaction was then quenched with NH3 in propanol and the resulting solution was loaded on a preparative HPLC to be purified. Following a work-up procedure similar to that for Compound D of Example 36, the title compound (13 mg, 30%) was obtained as a HCl salt. 1H NMR (DMSO-d6) δ 12.45 (s, 1H), 11.85 (s, 1H), 11.50 (br s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.90 (d, 1H), 7.50 (m, 2H), 7.40 (m, 2H), 7.20 (m, 2H), 4.50 (br s, 2H), 4.00 (m, 2H), 3.85 (s, 2H), 3.25-3.70 (m, 8H), 2.40 (s, 3H); MS(ESI+) m/z 583.2 (M+H)+.