Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][O:12][C:13]=1[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH:24]=3)[CH:21]=2)[NH:16][CH:15]=1.N1([O:39][S:40]([CH3:43])(=O)=[O:41])C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O>CN(C=O)C.CCN(C(C)C)C(C)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][O:12][C:13]=1[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[CH2:28][CH2:27][CH:26]([NH:29][S:40]([CH3:43])(=[O:41])=[O:39])[CH2:25][CH:24]=3)[CH:21]=2)[NH:16][CH:15]=1
Reactant: CS(=O)(=O)On1nnc2ccccc21
Reactant: NC1CC=C(c2cnc3[nH]cc(-c4oncc4-c4cccc(F)c4F)c3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC1CC=C(c2cnc3[nH]cc(-c4oncc4-c4cccc(F)c4F)c3c2)CC1
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a solution of 4-{3-[4-(2,3-Difluoro-phenyl)-isoxazol-5-yl]-1H-pyrrolo [2,3-b]pyridin-5-yl}-cyclohex-3-enylamine (47 mg, 0.12 mmol) in DMF (2 ml) was added methanesulfonic acid benzotriazol-1-yl ester (27 mg, 0.13 mmol) and Hunig base (10 drops) and stirred for 1 h. TFA was added, and the reaction mixture was purified by HPLC to give the methanesulfonamide (25.9 mg) in 46% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([NH2:12])=[C:5]2[C:13]#[N:14].[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br)([O-:17])=[O:16].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([NH2:12])=[C:5]2[C:13]#[N:14])([O-:17])=[O:16]
Reactant: Cn1c(N)c(C#N)c2cc(O)ccc21
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(N)c(C#N)c2cc(OCc3cccc([N+](=O)[O-])c3)ccc21
Reaction time: 2 h
Yield: 56.2 %

Procedure:
A solution of 5-hydroxy-2-amino-1-methyl-1H-indole-3-carbonitrile (100 mg; 0.53 mmol) and 3-nitrobenzyl bromide (130 mg; 0.6 mmol) in DMF (5 ml) was treated with Cs2CO3 (520 mg; 1.6 mmol) and the mixture was stirred for 2 hours. Water (80 ml) was added and the precipitate was filtered, taken up in methanol, filtered, washed and dried to give 5-(3-nitrobenzyloxy)-2-amino-1-methyl-1H-indole-3-carbonitrile (96 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].[C:9]([O-:12])(O)=[O:10].[Na+].[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C2C(=O)N(C([O-])=O)C=CC=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C1COCC1>[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:12][C:9]([NH:1][C@H:2]([C@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[O:10])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])n1cccc(CCCCCc2ccccc2)c1=O
Reactant: O=C([O-])O
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 89.6 %

Procedure:
To a stirred mixture of D-allo-threonine (0.10 g, 0.83 mmol) and NaHCO3 (0.11 g, 1.25 mmol) in H2O (3.5 mL), the crude mixture containing 5-phenyl-pentyl-2-pyridyl-carbonate and 5-phenyl-pentyl-2-oxopyridine 1-carboxylate (0.36 g, 1.25 mmol) in THF (3.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.23 g, 89%) as colorless oil, which was used in the next step without further purification. MS (ESI) m/z: 332 [M−Na]+, 327 [M−NH4]+; (ESI) m/z: 308 [M−H]−. 1H NMR (DMSO-d6) δ 1.08 (d, J=6.0 Hz, 3H), 1.28-1.39 (m, 2H), 1.59 (t, J=9.0 Hz, 4H), 2.57 (t, J=7.7 Hz, 2H), 3.80-4.00 (m, 4H), 7.10 (d, J=8.1 Hz, 1H), 7.13-7.22 (m, 3H), 7.22-7.31 (m, 2H), 12.33 (s, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH:2]=[CH2:3].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[O:12][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH:2]=[CH2:3]
Reactant: O=Cc1ccc(F)cc1
Reactant: C=CCOc1cc(C)cc(O)c1
Product: C=CCOc1cc(C)cc(Oc2ccc(C=O)cc2)c1

Procedure:
The product from Example 89A and 4-fluorobenzaldehyde were processed as in Example 61C to provide the title compound. MS (DCI) m/z 269 (M+H)+.
Reaction SMILES: Cl.Cl[C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[NH:16]([C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncnc2[nH]c3ccccc3c12
Agent: Cl
Solvent: CCO
Product: c1ccc(Nc2ncnc3[nH]c4ccccc4c23)cc1
Yield: 18.8 %

Procedure:
4-Chloroindolo[2,3-d]pyrimidine hydrochloride (R. G. Glushkov et. al., Khim.-Farm. Zh., 1967, 1(9), 25-32) (240 mg, 1 mmol) and aniline (0.27 mL, 3 mmol) in ethanol (1 mL) are heated under reflux for 6 h. The solvent is evaporated under reduced pressure, and the residue triturated with EtOAc to afford a tan powder which is filtered, and washed with cold ethanol. Recrystallization from acetone/pet. ether gives 4-anilinoindolo[2,3-d]pyrimidine (49 mg, 19%). 1H NMR (DMSO) δ1H, s), 8.84 (1H, s), 8.43 (1H, s), 8.37 (1H, d, J=8.0 Hz), 7.74 (2H, d, J=7.7 Hz), 7.52-7.08 (6H, m).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[Cl:7][CH2:8][CH2:9]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)C>[C:1]([O:6][CH2:9][CH2:8][Cl:7])(=[O:5])[C:2]([CH3:4])=[O:3]
Reactant: OCCCl
Reactant: CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)C(=O)OCCCl
Temperature: 25 °C

Procedure:
2-Chloroethyl pyruvate was prepared as follows: pyruvic acid (8.8 g, 100 mmol), 2-chloroethanol (10.45 g, 130 mmol) and p-toluenesulfonic acid monohydrate (1.9 g, 10 mmol) in 40 mL of benzene were heated under reflux with azeotropic dehydration for 5 h. The mixture was cooled to room temperature and diluted with 70 mL of diethyl ether. This organic solution was washed with 100 mL of saturated aqueous NaHCO3 and 100 mL of saturated aqueous NaCl. The organic layer was dried over anhydrous MgSO4, filtered and solvent removed on a rotary evaporator to give 2-chloroethyl pyruvate in quantitative yield, slightly contaminated with benzene and diethyl ether (as determined by 1H NMR). Aliquots used for biological analyses were cleared of diethyl ether and benzene by short path vacuum distillation.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=O)[C@@H:22]([NH:28][C:29](=[O:51])[C@H:30]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:20]1[OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:52][CH2:53][C:54]([OH:56])=[O:55].C(N(CC)CC)C>O1CCCC1.O>[C:54]([CH2:53][NH:52][C:25](=[O:27])[C@H:23]1[O:24][C@@H:19]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][CH:17]=[N:18][C:10]=3[NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:20]([OH:21])[C@@H:22]1[NH:28][C:29](=[O:51])[C@H:30]([CH2:42][C:43]1[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=1)[NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])([OH:56])=[O:55]
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2C(=O)O)cc1
Reactant: NCC(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2C(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.1 %

Procedure:
A solution of N-hydroxysuccinimide ester of 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-β-D-ribofuranuronic acid (295 mg) prepared in Example 53 (1) in tetrahydrofuran was added to a solution of glycine (30 mg) and triethylamine (0.085 ml) in water (5 ml). The mixture was stirred for 20 hours at room temperature and concentrated under reduced pressure to remove tetrahydrofuran. The aqueous solution was acidified with 1N hydrochloric acid and extracted with a mixed solvent (chloroform/ethanol=1/1). The extract was dried and evaporated to dryness. The residue was triturated in diethyl ether to give N-carboxymethyl-1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-β-D-ribofuranuronamide (244 mg), mp. 122°-130° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[O:41])[CH2:39]Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O(C1C=CC=CC=1C(O)=O)C1C=CC=CC=1>>[O:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[O:41])[CH2:39][N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(CCl)c1ccccc1Oc1ccccc1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: O=C(O)c1ccccc1Oc1ccccc1
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccccc1Oc1ccccc1

Procedure:
Using the procedure described in Example 5, treatment of L-proline-L-isoleucine benzylamide (200 mg, 0.63 mmol) with 2'-phenoxy-2-chloroacetophenone (233 mg, 0.95 mmol, 1.5 eq; prepared from 2-phenoxybenzoic acid by the method described in Example 1) provided 40 mg of L-isoleucine, N-[1-(2-(2-phenoxyphenyl)-2-oxoethyl)-L-prolyl] benzylamide as a foam.
Reaction SMILES: COP(=O)OC.[C:7](=O)([O-])[O-].[K+].[K+].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N:21]1[C:25]([CH3:26])=[C:24]([CH:27]=O)[N:23]=[C:22]1[CH3:29]>CO>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N:21]1[C:25]([CH3:26])=[C:24]([C:27]#[CH:7])[N:23]=[C:22]1[CH3:29]
Reactant: Cc1nc(C=O)c(C)n1-c1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: CO[PH](=O)OC
Agent: [K+]
Solvent: CO
Product: C#Cc1nc(C)n(-c2ccc(F)cc2F)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (0.37 g, 2 mmol) was dissolved in 20 mL methanol. Potassium carbonate (0.38 g, 3 mmol) was added. A solution of 1-(2,4-Difluoro-phenyl)-2,5-dimethyl-1H-imidazole-4-carbaldehyde (0.32 g, 1 mmol) in 5 ml methanol was added drop wise at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 15 ml water and extracted three times with ethyl acetate (15 ml each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10→50:50 gradient) and the desired compound was obtained as a light yellow solid (0.165 g, 52%), MS: m/e=233.1 (M+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][OH:12])[CH:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]([CH2:19][C:18]2[CH:30]=[CH:31][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][OH:12])[CH:5]=[CH:4][N:3]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: O=[N+]([O-])c1c(NO)ccnc1Cl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nccc(NO)c2[N+](=O)[O-])cc1

Procedure:
In step (2) of Reaction Scheme IV, an N-(2-chloro-3-nitropyridin-4-yl)hydroxylamine of Formula XXXVIII is reacted with bis-(4-methoxybenzyl)amine to provide an N-{2-[bis-(4-methoxybenzyl)amino]-3-nitropyridin-4-yl}hydroxylamine of Formula XXXIX. The reaction can be carried out by adding the bis-(4-methoxybenzyl)amine to a solution of a compound of Formula XXXVIII in a suitable solvent such as toluene in the presence of a base such as triethylamine. The reaction can be carried out at an elevated temperature (about 90° C.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][N:4]=1.CS(O[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=2)[CH2:22][CH2:21]1)(=O)=O.C(OC(N1CCC(N2C=NC(COS(C)(=O)=O)=N2)CC1)=O)(C)(C)C>>[CH2:32]([C:29]1[CH:28]=[N:27][C:26]([N:23]2[CH2:24][CH2:25][CH:20]([N:5]3[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([C:2]([F:1])([F:13])[F:14])=[N:4]3)[CH2:21][CH2:22]2)=[N:31][CH:30]=1)[CH3:33].[CH2:32]([C:29]1[CH:28]=[N:27][C:26]([N:23]2[CH2:24][CH2:25][CH:20]([N:4]3[C:3]([C:2]([F:1])([F:13])[F:14])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[N:5]3)[CH2:21][CH2:22]2)=[N:31][CH:30]=1)[CH3:33]
Reactant: CCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: CC(C)(C)OC(=O)N1CCC(n2cnc(COS(C)(=O)=O)n2)CC1
Product: CCOC(=O)c1cn(C2CCN(c3ncc(CC)cn3)CC2)nc1C(F)(F)F
Product: CCOC(=O)c1cnn(C2CCN(c3ncc(CC)cn3)CC2)c1C(F)(F)F

Procedure:
The compound was synthesized using ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate and 1-(5-ethylpyrimidin-2-yl)piperidin-4-yl methanesulfonate in a manner similar to that described in Intermediate 1, Step 1. The reaction afforded two regioisomers, ethyl 1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate and ethyl 1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate which were separated by flash column chromatography on silica gel.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:14]([N+:23]([O-:25])=[O:24])=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[C:14]([N+:23]([O-:25])=[O:24])=[C:15]2[C:20](=[CH:21][CH:22]=1)[N+:19]([O-:9])=[CH:18][CH:17]=[CH:16]2
Reactant: O=[N+]([O-])c1c(Cl)ccc2ncccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1c(Cl)ccc2c1ccc[n+]2[O-]
Reaction time: 6 h
Yield: 83.5 %

Procedure:
m-Chloroperbenzoic acid (70–75% by wt, 2.7 g, 15.6 mmol) was added in portions to a stirred, ambient temperature solution of 6-chloro-5-nitroquinoline (2 g, 9.6 mmol) in CHCl3 (15 mL). The mixture was stirred for 6 h. After this time, more CHCl3 was added, followed by 30 mL of a saturated aqueous solution of Na2CO3 and 1 mL 1M NaOH. The mixture was separated and the aqueous phase extracted with CHCl3 (×2). The organic phases were combined and washed with a saturated aqueous solution of Na2CO3, H2O and brine. The organic phase was dried (MgSO4) and the solvent removed in vacuo to give 6-Chloro-5-nitroquinoline-N-oxide as a yellow solid (1.8 g, 84%); H (300 MHz; CDCl3) 7.6 (1H, m), 7.7 (1H, d), 7.95 (1H, d), 8.65 (1H, d) and 8.75 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)=O.O.[OH-].[Li+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[S:11][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[CH2:28][CH2:27][C@H:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)CBr)cc2)CC1
Reactant: COc1cccc(NC(N)=S)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc(Nc2nc(-c3ccc([C@H]4CC[C@H](CC(=O)O)CC4)cc3)cs2)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1-(3-Methoxyphenyl)-2-thiourea (0.01 g, 0.054 mmol) was added to a solution of the product from Example 48A (0.02 g, 0.054 mmol) in ethanol (0.5 mL) and heated at 80° C. for 1 h. The solvent was then removed in vacuo and the residue taken up in tetrahydrofuran (1 mL) and water (0.5 mL). Lithium hydroxide monohydrate (0.005 g, 0.1 mmol) was added to the reaction mixture and stirred at 50° C. for 3 h. The solvents were then removed and the residue purified by RP-HPLC to afford the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.09-1.18 (m, 2 H), 1.45-1.54 (m, 2 H), 1.62-1.69 (m, 1 H), 1.70-1.77 (m, 1 H), 1.80-1.88 (m, 4 H), 2.13 (d, J=7 Hz, 2 H), 3.78 (s, 3 H), 6.54 (dd, J=8.24, 1.83 Hz, 1 H), 7.10-7.16 (m, 1 H), 7.20-7.27 (m, 1 H), 7.29 (d, J=8.24 Hz, 2 H), 7.51-7.56 (m, 1 H), 7.79-7.83 (d, J=8.24 Hz, 2 H), 10.25 (s, 1 H), 1.2.05 (s, 1 H): MS (ESI) m/e 423.2 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH2:7][C:6]2([CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12](/[CH:18]=[CH:19]/[C:20](O)=[O:21])[CH:13]=3)[O:8]2)[CH2:5]1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:37][O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1>C(Cl)Cl>[C:1]([N:4]1[CH2:7][C:6]2([CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12](/[CH:18]=[CH:19]/[C:20]([NH:37][O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)=[O:21])[CH:13]=3)[O:8]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Yield: 30 %

Procedure:
A suspension of (E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (100 mg, 0.30 mmol) in DCM (3 ml) was treated with TEA (0.060 ml, 0.49 mmol) and then with EDC (94 mg, 0.49 mmol), HOBt (67 mg, 0.49 mmol) and NH2OTHP (50 mg, 0.43 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (36 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>O1CCOCC1>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: Nc1ccccc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: O
Solvent: C1COCCO1
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2ccccc2)nc(N2CCOCC2)n1
Yield: 49.1 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (92 mg, 0.25 mmol) and aniline (58 mg, 0.625 mmol) in dioxane (5 mL) was heated under reflux for 1 hr and cooled. Dilution with water gave a white precipitate, which was recrystallised from MeOH to give 52 mg (49% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-phenyl-1,3,5-triazin-2-amine: mp 171-174° C.; 1H NMR (CDCl3) δ 8.40 (m, 1H), 7.89 (m, 1H), 7.58 (t, JHF=54.7 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.43-7.38 (m, 4H), 7.20 (t, J=7.3 Hz, 1H), 7.09 (br, exchangeable with D2O, 1H), 3.93 (m, 4H), 3.81 (m, 4H); Anal. Calc. for C21H19F2N7O: C, 59.6; H, 4.5; N, 23.2. Found: C, 59.6; H, 4.5; N, 23.3%.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[N-:5]=[N+:6]=[N-:7].[Na+].[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>O>[C:15]1([CH3:16])[CH:17]=[CH:18][C:12]([S:9]([O:4][CH2:3][CH2:2][N:5]=[N+:6]=[N-:7])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: OCCBr
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCN=[N+]=[N-])cc1
Reaction time: 8 h
Yield: 71.8 %

Procedure:
A solution of 2-bromoethanol (5.06 g; 40.4 mmol) and sodium azide (3.12 g; 48 mmol; 1.2 equiv) in water (15 ml) is stirred at 60° C. for 4 hours, extracted with dichloromethane (4×20 ml), dried over sodium sulphate, filtered and concentrated (it should be noted that 2-azidoethanol is too volatile to be dried under a vane pump vacuum). The oily crude product is dissolved in pyridine (20 ml) at 0° C. and tosyl chloride (7.2 g; 48 mmol; 1.2 equiv) is added in small portions. The solution is taken to ambient temperature and stirred overnight. Water (10 ml) is then added and the product is extracted with dichloromethane (3×20 ml), dried over sodium sulphate and concentrated under reduced pressure in order to produce the title compound (7 g; 29 mmol; 72%).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][CH:14]=[CH:15][C:8]=12.[N+:16]([O-])([OH:18])=[O:17]>O>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:8]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2nccc(Cl)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Into concentrated sulfuric acid (150 mL) was added 4-chloro-1H-pyrrolo[2,3-b]pyridine (50.0 g) in portions while maintaining the internal temperature of the mixture below 10° C. (Note: exothermic upon addition). A mixture of concentrated nitric acid (30.0 mL) and concentrated sulfuric acid (60.0 mL) was added slowly while maintaining the internal temperature of the mixture below 10° C. (Note: exothermic upon addition). The reaction mixture was stirred at 0° C. for 30 min. Cold water (750 mL) was added slowly while maintaining the internal temperature below 20° C. (Note: exothermic upon addition). The resulting solid was collected by filtration and washed with a pH 7 buffer solution, water, and then acetonitrile. The product was collected by filtration and dried in a vacuum oven at 50° C. overnight to give the 52 g (92% yield) of 4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine as an light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.5 (s, 1H), 8.91 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 7.50 (d, J=5.2 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) δ 148.0, 145.7, 134.7, 132.5, 127.2, 120.9, 110.0. HRMS calcd. For C7H3ClN3O2 [M-H]−: 199.9919, found 199.9921.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.Cl.[NH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 1.2 g; 3.47 mmol) in THF (100 ml) was treated with tert-butyl 3-aminopropanoate hydrochloride (800 mg; 4.4 mmol) and diisopropylamine (2 ml; 14.3 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.