Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([O:10]/[N:11]=[C:12](/[C:32]1[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=1)\[C:13]([NH:15][C@H:16]1[C@@H:19]([CH2:20][N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[N:18]([S:27]([OH:30])(=[O:29])=[O:28])[C:17]1=[O:31])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:45])=[O:5])/[C:13](=[O:14])[NH:15][C@H:16]2[C@@H:19]([CH2:20][N:21]3[CH2:25][CH2:24][NH:23][C:22]3=[O:26])[N:18]([S:27]([OH:30])(=[O:29])=[O:28])[C:17]2=[O:31])[N:33]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCNC2=O)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CCNC1=O)c1csc(N)n1)C(=O)O
Yield: 6.3 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxoimidazolidin-1-yl)methyl)azetidine-1-sulfonic acid (99 mg, 0.147 mmol), DCM (1.47 mL) and TFA (566 μl, 7.35 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (4.8 mg) as a white powder. LCMS: Rt=0.31 min, m/z=520.0 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.25 (dd, J=9.0, 5.0 Hz, 1H), 6.83 (s, 1H), 5.21 (dd, J=9.0, 5.8 Hz, 1H), 4.06-4.00 (m, 1H), 3.65 (dd, J=14.5, 4.7 Hz, 1H), 3.33-3.30 (m, 1H assumed; obscured by water), 3.25 (dd, J=14.5, 6.9 Hz, 2H assumed; obscured by water), 3.17 (ddd, J=16.7, 8.6, 6.7 Hz, 2H), 1.43 (s, 3H), 1.42 (s, 3H).
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1>CO.O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1
Reactant: Cc1cc(N)no1
Reactant: O=CC(CO)OC(C=O)n1ccc(=O)[nH]c1=O
Solvent: O
Solvent: CO
Product: Cc1cc(N2C(O)[C@H](n3ccc(=O)[nH]c3=O)O[C@H](CO)C2O)no1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.7 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)pyrimidineacetaldehyde, (uridinedialdehyde), (4.0 g) was dissolved in a mixture of methanol (30 ml) and water (30 ml). To the solution was added 3-amino-5-methylisoxazole (1.62 g). The mixture was stirred at ambient temperature for five hours and evaporated in vacuo. The residue was triturated with acetone to give 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(5-methylisoxazol-3-yl)morpholin-2-yl]uracil (4.2 g).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[C@@H:24](O)[CH2:23]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:7]([O:9][C@@H:24]2[CH:25]3[CH2:28][CH2:29][N:22]([CH2:27][CH2:26]3)[CH2:23]2)=[O:8])[C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1cccc(F)c1)c1csc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cccc(F)c1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A mixture of 2-(benzo[b]thiophen-3-yl)-2-(3-fluorophenylamino)acetic acid (I40) (677 mg, 2.25 mmol), (R)-quinuclidin-3-ol (343 mg, 2.70 mmol), HOBT (413 mg, 2.70 mmol), and DCC (556 mg, 2.70 mmol) in THF (20 ml) was stirred at room temperature overnight. THF was evaporated, and the crude product was partitioned between EtOAc and 1M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH=98/2 to 95/5) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(3-fluorophenylamino)acetate (421 mg, 45.6% yield over two steps).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH:7]=O)[N:4]([CH3:9])[N:3]=1.[Cl-].[CH3:11][C:12]1[N:17]2[N:18]=[C:19]([CH2:21][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:20]=[C:16]2[C:15]([CH3:41])=[N:14][CH:13]=1>>[Br:1][C:2]1[N:6]=[C:5](/[CH:7]=[CH:21]/[C:19]2[N:20]=[C:16]3[C:15]([CH3:41])=[N:14][CH:13]=[C:12]([CH3:11])[N:17]3[N:18]=2)[N:4]([CH3:9])[N:3]=1
Reactant: Cn1nc(Br)nc1C=O
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Product: Cc1ncc(C)n2nc(/C=C/c3nc(Br)nn3C)nc12
Yield: 67.1 %

Procedure:
Was prepared in the same manner as described in Example 1g) using 3-bromo-1-methyl-1H-1,2,4-triazole-5-carbaldehyde (218 mg, 1.15 mmol, Eq: 1.00) and ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (527 mg, 1.15 mmol, Eq: 1.00) as starting materials. Chromatography afforded 2-[(E)-2-(5-bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (258 mg/67.3%) as a white solid. MS: m/e=336.0334.1 (M+H+), mp: 199.4° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10]([OH:12])=O)[C:6]=1[CH3:7].[CH3:44][CH:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:48][CH2:47][NH:46]1>>[CH2:39]([N:34]([CH2:35][CH2:36][CH2:37][CH3:38])[C:33]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])=[CH:13][C:9]=2[C:10]([N:46]2[CH2:47][CH2:48][C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:45]2[CH3:44])=[O:12])[N:4]=1)=[O:43])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Reactant: CC1NCCc2ccccc21
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2C)c(C)c1Cl
Yield: 31.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 93B, 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 32 mg, 0.051 mmol) and 1-methyl-1,2,3,4-tetrahydroisoquinoline (Parkway Scientific, 8 mg, 0.056 mmol) were converted to the title compound (12 mg, 31%) following purification by preparative HPLC. 1H NMR (DMSO-d6, mixture of amide rotamers) δ 8.65 (s, 1H), 8.21 (d, J=8.1 Hz, 2H), 8.16-8.03 (m, 4H), 8.01-7.94 (m, 1.5H), 7.91 (br s, 0.5H), 7.77-7.61 (m, 3H), 7.27-6.93 (m, 2H), 5.48-5.31 (m, 0.5H), 3.68-3.55 (m, 1H), 3.17-2.57 (m, 4.5H), 2.55 (t, J=5.5 Hz, 3H), 2.20 (s, 3H), 1.53-1.36 (3.5H), 1.29-1.23 (m, 2.5H), 1.21-1.12 (m, 4H), 0.95-0.82 (m, 3.5H), 0.66 (d, J=7.3 Hz, 3H), 0.56 (br s, 0.5H); MS(ESI+) m/z 754.3 (M+H)+.
Reaction SMILES: [Na:1].COC1OCC([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[CH3:31][C:32]1(CO)[O:37][CH2:36][CH2:35][CH2:34][O:33]1>>[Na:1].[CH3:30][C:13]1[C:14]([CH2:18][S:19]([C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[O:20])=[N:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:10][C:32]1([CH3:31])[O:37][CH2:36][CH2:35][CH2:34][O:33]1
Reactant: CC1(CO)OCCCO1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Agent: [Na]
Product: Cc1c(OCC2(C)OCCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 8.6 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using (2-methyl-1,3-dioxan-2-yl)methanol obtained in the step (33a) to obtain the title compound (220 mg, total yield: 8.6%) as a light yellow solid.
Reaction SMILES: O[C@@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:39]([OH:42])(=[S:41])[CH3:40]>O1CCCC1>[C:39]([S:41][C@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1)(=[O:42])[CH3:40]
Reactant: CC(O)=S
Reactant: O=C1C[C@H](O)CN1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1CNC(=O)C1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
380 mg of (4S)-4-hydroxy-2-oxopyrrolidine were suspended in 21 ml of anhydrous tetrahydrofuran, and 1.18 g of triphenylphosphine were added to the suspension at room temperature. 783 mg of diethyl azodicarboxylate were then added dropwise to the solution, whilst maintaining a temperature of -30° C. The mixture was then gradually heated to 4° C., after which the mixture was stirred at the same temperature for 30 minutes to produce a homogeneous mixture. At the end of this time, the reaction mixture was cooled to -20° C., and then 320 μl of thioacetic acid were added dropwise to the cooled mixture. The resulting mixture was gradually heated to a temperature equivalent to ice-cooling; and the mixture was stirred for 1.5 hours at that temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and then subjected to column chromatography (Merck 9385, 60 ml) through silica gel using a gradient elution method, with mixtures of benzene and acetonitrile ranging from 2:1 and 1:1 by volume as the eluent. The desired fraction was concentrated by evaporation under reduced pressure to give 69 mg of a crystalline residue. This residue was recrystallized from a mixture of ethyl acetate and cyclohexane to give 54 mg of the title compound as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12](O)=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5].CN(C)C=O.S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12]([Cl:30])=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reaction time: 2 h

Procedure:
3.37 g of 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid are suspended in 100 ml of toluene; 0.1 ml of dimethylformamide and 1.64 g of thionyl chloride are added and the whole is heated to 80°, stirred for 2 hours at 80°-90° and concentrated to dryness by evaporation under reduced pressure. 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid chloride is obtained which can be used without being further treated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Yield: 109.2 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 4-chlorobenzoyl chloride (29 μL, 0.229 mmol), 44.8 mg (>100%) of the title compound were recovered.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[K+].[Br-]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:31]3[CH2:32][CH2:33][N:28]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][N:22]=4)[CH2:29][CH2:30]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: c1cnc(N2CCNCC2)cn1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(c2cnccn2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(pyrazin-2-yl)-piperazine White crystals, m.p. 160-161° C.; HPLC-MS: m/z=446 (M+1) at Rt=4.0 min.; 1H NMR (DMSO-d6): δ 8.60-8.57 (m, 1H), 8.39-8.36 (m, 1H), 8.27-8.22 (dd-like, 1H), 8.14-8.11 (m, 1H) 7.91-7.87 (d-like, 1H), 7.29-7.21 (m, 5H), 3.80-3.64 (br, 6H), 3.64-3.50 (br, 2H); IR (KBr): ν 1737, 1714 (C═O) cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]O)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[BrH:16]>O>[Br:16][CH2:12][CH2:11][CH2:10][N:6]1[C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=2[NH:8][C:7]1=[O:9]
Reactant: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Reactant: Br
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCBr

Procedure:
A mixture of 9.3 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one and 83 parts of a hydrobromic acid solution 48% in water was stirred and refluxed for 6 hours. The reaction mixture was cooled and allowed to crystallize overnight at room temperature. The precipitated product was filtered off and stirred a few times in 100 parts of water till the pH of the filtrate was greater than 2. The product was stirred and refluxed for 1 hour in 55 parts of chlorobenzene with 1.3 parts of activated charcoal. The latter was filtered off and the filtrate was allowed to crystallize overnight in an ice-box. The product was filtered off and recrystallized twice: first from chlorobenzene (activated charcoal) and then from methylbenzene (activated charcoal), yielding 4.9 parts of 1-(3-bromopropyl)-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 161.5° C. (intermediate 29).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:34][CH2:33][C:28]4([O:32][CH2:31][CH2:30][O:29]4)[CH2:27][CH2:26]3)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:36].C(OCC)(=O)C.[Cl-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:36])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:34][CH2:33][C:28]4([O:32][CH2:31][CH2:30][O:29]4)[CH2:27][CH2:26]3)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2C1CCC2(CC1)OCCO2
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2C1CCC2(CC1)OCCO2
Temperature: 120 °C
Yield: 81 %

Procedure:
A mixture of 5-[4-(benzyloxy)phenyl]-4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidine (1.925 g, 4.01 mmol) and concentrated ammonium hydroxide (50 ml) in dioxane (50 mL) was heated at 120° C. in a pressure vessel for 20 hours. The reaction mixture was allowed to cool to room temperature. Ethyl acetate (300 mL) and saturated sodium chloride aqueous solution (300 mL) were added. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (700 mL). The organic layers were combined, washed with water, dried over magnesium sulfate, and the solvent removed under reduced pressure. The compound was purified by flash chromatography on silica using 5% methanol in dichloromethane to give 1.457 g (81%) of 5-[4-(benzyloxy)phenyl]-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.13(s, 1H), 7.49-7.31(m, 8H), 7.121-7.100(d, 2H, J=8 Hz), 6.02(br s, 2H), 5.149(s, 2H), 4.681-4.620 (m, 1H), 3.94-3.88(m, 4H), 2.12-2.03(m, 2H), 1.93-1.90(m, 2H), 1.82-1.71(m, 4H); Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 6.924 min.
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:13])[CH:2]([CH3:4])[CH3:3].[C:42]([NH:48][C@H:49](C(O)=O)[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>>[CH3:41][C:38]1[CH:37]=[CH:36][C:35]([S:32]([N:5]([C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@@H:49]([NH:48][C:42]([C:43]([CH3:46])([CH3:45])[CH3:44])=[O:47])[CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:13])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:34])=[O:33])=[CH:40][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CC(C)(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NC(=O)C(C)(C)C)C(=O)O)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-pivaloyl-L-phenylalanine (300 mg, 1.2 mmol). The final product was purified by preparative HPLC to yield 49 mg (66%) of the desired material.
Reaction SMILES: C([NH:4][C:5]1[N:14]=[C:13](C2N=CNN=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:11]=2)[N:6]=1)(=O)C.[CH:27]([OH:30])([CH3:29])[CH3:28]>>[NH2:4][C:5]1[N:14]=[C:13]([O:30][CH:27]([CH3:29])[CH3:28])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:11]=2)[N:6]=1
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2cc(-c3ccc(F)cc3)ccc2n1
Reactant: CC(C)O
Product: CC(C)Oc1nc(N)nc2ccc(-c3ccc(F)cc3)cc12
Yield: 85 %

Procedure:
This compound, synthesized from 2-acetamido-6-(4-fluorophenyl)-4-(1,2,4-triazolyl)-quinazoline and isopropanol in 85% yield using the same procedure as in example 18, was characterized by its mass spectrum as follows: MS (m/z): 283 ([M+H]+, 100).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22]C(=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36](=[O:41])[C:35]2([CH3:43])[CH3:42].[I-].[K+]>CO.ClCCl>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:29][CH2:30][CH2:31][C:32]3[CH:33]=[C:34]4[C:38](=[CH:39][CH:40]=3)[NH:37][C:36](=[O:41])[C:35]4([CH3:42])[CH3:43])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC1(C)C(=O)Nc2ccc(CCCCl)cc21
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCc3ccc4c(c3)C(C)(C)C(=O)N4)c2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Under nitrogen atmosphere, add potassium hydroxide (138 mg, 2.46 mmol) to a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (375 mg, 0.97 mmol) in methanol (10 mL). Heat under reflux for 2 h then add further potassium hydroxide (159 mg, 2.83 mmol) and continue heating under reflux for another 6 h. Cool the reaction mixture and add dropwise via cannula a solution of 5-(3-chloropropyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (245 mg, 1.03 mmol) in methanol (10 mL). Stir at ambient temperature overnight then heat at 50° C. for 5 h. Add potassium iodide (186 mg, 1.12 mmol) to the reaction mixture and then heat under reflux for 5 h. Concentrate in vacuo and partition the residue between water (100 mL) and EtOAc (50 mL). Extract the aqueous phase with EtOAc (2×50 mL). Wash the combined extracts with brine (50 mL), dry over MgSO4, filter and concentrate in vacuo to obtain the crude mixture as a yellow oil. Dilute this oil with dichloromethane then re-concentrate in vacuo and repeat until a solid remains. Dry the solid in a vacuum oven to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid (481 mg) that was used without further purification. MS (ES+) m/z: 537 (M+Na)÷.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][N:7]1[CH2:10][CH:9]([NH:11]C(=O)OC(C)(C)C)[CH2:8]1.[ClH:24]>CO.O1CCOCC1>[ClH:24].[F:22][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][N:7]1[CH2:8][CH:9]([NH2:11])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CN(Cc2cccc(C(F)(F)F)c2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1CN(Cc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of product from Example 180A (0.14 g) in methanol (5 mL) was added 4 N HCl in dioxane (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.81 (bs, 2H), 7.95 (m, 1H), 7.84 (m, 2H), 7.71 (t, J=7.73 Hz, 1H), 4.63 (s, 2H), 4.23 (m, 5H); MS (DCI) m/z 231 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.ClCCl.[C].[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnccc1Nc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Nc1cnccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
4-Phenylamino-3-nitropyridine (1.40 g, 6.51 mmol) was dissolved in the mixed solvent of 15 ml of ethanol and 10 ml of dichloromethane. After the atmosphere was replaced with nitrogen, 0.10 g of 10% palladium-carbon was added thereto. After the atmosphere was replaced with hydrogen, hydrogen addition was conducted with stirring at room temperature for about 15 hours. Palladium-carbon was removed by filtration and the filtered cake was washed with ethanol. The filtrate and the washings were combined and then concentrated. The residue was purified by silica gel column chromatography [eluent: dichloromethane: methanol=2:1 (v/v)] to obtain 1.07 g of a light brown solid (yield: 88.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][C:14]=1[F:23].[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][C:14]=1[F:23]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)OC)cc2F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(C)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-[2,6-difluoro-4-(1-hydroxyethyl)phenyl]-5-fluoro-pyridine-2-carboxylate (1.21 mmol, 376 mg; penultimate intermediate en route to Intermediate 136) in N,N-dimethylformamide (50 mL) at 0° C. was added sodium hydride (60 mass % in mineral oil, 1.5 equiv., 1.81 mmol, 72.5 mg). The mixture was stirred for 2 minutes, then iodomethane (3.0 equiv., 3.62 mmol, 0.226 mL) was added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica eluted with 0 to 50% EtOAc in Heptane to provide methyl 6-(2,6-difluoro-4-(1-methoxyethyl)phenyl)-5-fluoropicolinate (392 mg, 63%). This ester was diluted with MeOH (15 mL) and water (5 mL) and lithium hydroxide (60 mg) was added. The mixture was stirred overnight at rt. The reaction was quenched by the addition of 1 N HCl(aq), then the mixture was diluted with EtOAc and washed with brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo to provide the title compound (quant) which was used without purification.