Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]([Cl:18])=[C:10]([N+:19]([O-])=O)[CH:9]=1.O.[NH4+].[OH-]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[NH2:19][C:10]1[CH:9]=[C:8]([Br:7])[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]=1[Cl:18]
Reactant: COC(=O)c1nc(Br)cc([N+](=O)[O-])c1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc(Br)cc(N)c1Cl
Reaction time: 0.25 h

Procedure:
To a solution of titanium tetrachloride (0.015 mol, 2.8 g) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (0.0175 mol, 0.7 g). The black slurry was stirred 15 min before adding methyl 6-bromo-3-chloro-4-nitropyridine-2-carboxylate, N-oxide (0.007 mol, 2.3 g) in THF (25 mL). The solution was stirred 1 hr before pouring into 1:1 H2O/NH4OH and filtering. The filtrate was extracted with EtOAc (2×75 mL). The organic phase was dried (Na2SO4), and concentrated. The red solid was chromatographed over silica in 4:1 EtOAc/hexane to give methyl 4-amino-6-bromo-3-chloropyridine-2-carboxylate (0.003 mol, 0.8 g); mp 194-5° C. 1H NMR(CDCl3): δ 3.95 (3H, s), 5.3 (2H, bs), 6.9 (1H, s).
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[NH2:8][C:9]1[S:10][C:11]([C:20](=[O:24])[N:21]([CH3:23])[CH3:22])=[C:12]([CH3:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(OCC)(OCC)OCC>[CH2:1]([O:4][CH:5]=[N:8][C:9]1[S:10][C:11]([C:20](=[O:24])[N:21]([CH3:22])[CH3:23])=[C:12]([CH3:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(N)sc(C(=O)N(C)C)c1C
Solvent: CCOC(OCC)OCC
Product: CCOC=Nc1sc(C(=O)N(C)C)c(C)c1C(=O)OCC
Yield: 96 %

Procedure:
2.0 ml of acetic anhydride were added to 30.6 g (119 mmol) of 2-amino-3-carboethoxy-4-methyl-5-dimethylcarbamoyl-thiophene in 150 ml of triethyl orthoformate, and the mixture was boiled under nitrogen and at reflux for 2 h. The mixture was then evaporated right down at 80° C. on a rotary evaporator. 35.6 g (96%) of crude product were isolated as a dark oil, which is sufficiently pure for further reaction.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[CH:10]=1)=[O:5])C.[OH-].[K+]>O.C(O)C>[CH:12]([C:8]1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=1[CH3:11])=[O:13]
Reactant: CCOC(=O)c1cc(C)c(C=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)[nH]c1C=O
Temperature: 100 °C
Yield: 99.4 %

Procedure:
To a solution of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.8 g, 4.4 mmol) in 35 mL of water and 15 mL of ethanol was added potassium hydroxide (0.5 g, 8.9 mmol). The reaction mixture was heated to 100° C. for 1 h, cooled to room temperature, and evaporated ethanol. The water layer was acidified to pH=3 using 2N hydrogen chloride solution. The precipitate was filtered and washed with water to afford 0.67 g (68%) of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid as a tan solid.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][C@H:6]1[N:13]1[CH:20]=[CH:19][C:17]([NH2:18])=[N:16][C:14]1=[O:15])[CH2:2][CH3:3].C[Si](Cl)(C)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[NH4+].[OH-]>O.N1C=CC=CC=1>[C:26]([NH:18][C:17]1[CH:19]=[CH:20][N:13]([C@@H:6]2[O:7][C@H:8]([CH2:11][OH:12])[C@@H:9]([OH:10])[C@H:5]2[O:4][CH2:1][CH2:2][CH3:3])[C:14](=[O:15])[N:16]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Reaction time: 0.5 h

Procedure:
To the 2'-O-propylcytidine reaction mixture of Example 82 in an ice bath was added pyridine (60 ml) and trimethylsilyl chloride (60 ml). The reaction was stirred for 30 mins followed by the addition of benzoyl chloride (55 ml). The resulting reaction mixture was stirred for 2.5 hrs and then cooled in an ice bath. H2O (100 ml) and conc. NH4OH (100 ml) were added. After stirring for 30 mins, the reaction mixture was evaporated and the residue partition between H2O and CH2Cl2. The organic phase was washed once with dil Na2CO3, once with dil HCl, dried over MgSO4 and evaporated. The resulting residue was loaded on a silica gel column (150 g) and eluted with first CH2Cl2 then 5 to 10% MeOH in CH2Cl2 as the elution solvent. The product containing fractions were evaporated to a foam. The foam was crystallized from EtOAc/Hexanes to give the product (6.5 g total) in several crystal batches.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)(=[O:4])[CH3:3].N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:20].O>ClCCl.C(OCC)(=O)C>[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:20])[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(NC(=O)Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-acetyl-4-aminopiperidine hydrochloride (0.4 g) in dichloromethane (5 ml) were added in turn pyridine (0.54 ml) and 4-fluorophenyl chloroformate (0.29 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour, which was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give 1-acetyl-4-(4-fluorophenoxycarbonylamino)piperidine (347 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Yield: 53.3 %

Procedure:
To a solution of (2R)-2-methyl-piperazine (4.5 g, 45 mmol) in ethanol (80 mL) was added 4-fluorobenzyl chloride (5.38 mL, 45.0 mmol) and sodium hydrogen carbonate (11.3 g, 135 mmol). The reaction was refluxed overnight, cooled and concentrated. The remaining residue was diluted with dichloromethane and washed with water. The organic layer was separated and concentrated to give a clear oil. Chromatography on silica gel gave the title compound (5.0 g).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21].C1C(=O)N([I:29])C(=O)C1.FC(F)(F)C(O)=O>CN(C=O)C>[F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:29])=[CH:17][C:16]=1[F:21]
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.2 %

Procedure:
To a solution of 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid (7.22 g, 24.88 mmol) in DMF (50 mL) was added NIS (6.08 g, 26.37 mmol) followed by trifluoroacetic acid (1.0 mL). After stirring for 5 h at ambient temperature, the reaction was quenched by saturated NH4Cl (aq.). The solution was extracted with ethyl acetate (150 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) successively, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50:1, v/v) and gave the desired product (brown solid, 6.34 g, 61.2% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.58 (s, 1H), 8.18 (s, 1H), 7.58 (dd, J=11.0, 1.7 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 6.55 (m, 1H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:11]=2[C:12](OC)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[F-].[Na+].O>CCOCC>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:11]=2[CH2:12][OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(F)c1NCCN1CCCCC1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: OCc1cccc(F)c1NCCN1CCCCC1
Temperature: 0 °C
Yield: 6799.2 %

Procedure:
A solution of methyl 2-(2-(piperidin-1-yl)ethylamino)-3-fluorobenzoate (740 mg, 2.640 mmol) in Et2O (30 mL) at −20° C. was treated with LAH (128 mg, 3.372 mmol). After 1.5 hours additional LAH (20 mg, 0.5269 mmol) was added and the reaction was warmed to 0° C. At 0° C., the reaction was diluted with Et2O (80 mL), then NaF and water were added with vigorous stirring until a white ppt formed and the solution cleared. The solution was decanted and evaporated under vacuum. The crude material was purified on a 12 g Redisep ISCO column with 0-10% MeOH in CH2Cl2 over 40 CV to yield (2-(2-(piperidin-1-yl)ethylamino)-3-fluorophenyl)methanol (453 mg, 179.5 mmol) as an off-white solid. FIA: 253.19 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][CH:13]=2)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>C(Cl)Cl>[Br:40][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([Cl:1])[N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cc(Cl)nc(-c2ccc(CO)cc2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)nc(-c2ccc(CBr)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of methyl 2-chloro-6-(4-(hydroxymethyl)phenyl)isonicotinate (0.67 g, 2.418 mmol) in DCM (10 mL), triphenyl phosphine (1 g, 3.86 mmol) and carbon tetrabromide (1.63 g, 3.87 mmol) were added at 0° C. and reaction mass stirred for overnight at rt. On completion, reaction mass was concentrated and purified by column chromatography over silica gel affording methyl 2-(4-(bromomethyl)phenyl)-6-chloroisonicotinate (0.53 g, 64%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[CH:39][C:38]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:41]4[CH:40]=[CH:39][C:38]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[C:37]([O:36][CH3:35])[CH:42]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=3)(=[O:26])=[O:27])[CH:9]=2)[CH:12]=[N:13]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NS(C)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cc(F)cc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1NS(C)(=O)=O
Yield: 26.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 example 71) (150 mg, 0.38 mmol) was coupled with N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 65C) (149 mg, 0.45 mmol) using sodium carbonate (121 mg, 1.14 mmol) and Pd(PPh3)2Cl2 (2 mg, 0.001 mmol) in DME/water (10/1 ml) to afford 98 mg (26.2% yield) after purification by column (Silica gel 60/120) using 65% ethyl acetate in hexane as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13]C1C=CC([N+]([O-])=O)=CC=1)=[O:12].[CH:40]1([CH2:43][O:44][C:45]2[CH:50]=[C:49]([CH2:51]O)[CH:48]=[CH:47][C:46]=2[N:53]([S:61]([CH3:64])(=[O:63])=[O:62])C(=O)OC(C)(C)C)[CH2:42][CH2:41]1.Cl.O1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13][CH2:51][C:49]1[CH:48]=[CH:47][C:46]([NH:53][S:61]([CH3:64])(=[O:63])=[O:62])=[C:45]([O:44][CH2:43][CH:40]2[CH2:42][CH2:41]2)[CH:50]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N(c1ccc(CO)cc1OCC1CC1)S(C)(=O)=O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(COC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.7 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine 1-oxide (prepared in an analogous manner as described in Scheme 3, Step 1) (0.150 g, 0.256 mmol) in DCM (10 ml), DMAP (0.0156 g, 0.128 mmol) was added followed by tert-butyl 2-(cyclopropylmethoxy)-4-(hydroxymethyl)phenyl(methylsulfonyl)carbamate (0.124 g, 0.333 mmol), and the resulting mixture was stirred at RT for 3 hours. HCl 4M in dioxane (3 ml, 12 mmol) was added and the reaction was stirred at RT for additional 5 hours. The solvent was removed under vacuum and the residue was purified by flash chromatography on silica gel column (DCM:MeOH=10:0.15). A further purification by flash chromatography on silica gel column (DCM:acetone=10:1) was required to obtain (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(cyclopropylmethoxy)-4-(methylsulfonamido)-benzyloxy)carbonyloxy)ethyl)pyridine 1-oxide as a white solid (0.073 g, 0.102 mmol, 39.7% yield, MS/ESI+ 716.93 [MH]+, [αD]=−11.84, c=0.495, DCM).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1O
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(OCc2ccccc2)ccc1OC
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.2 %

Procedure:
To a suspended solution of methyl 5-benzyloxy-2-hydroxybenzoate (3.91 g) and cesium carbonate (6.41 g) in acetone (100 ml) was added methyl iodide (1.41 ml), and the mixture was stirred at 50° C. for 6 hr. The reaction mixture was concentrated, dissolved again in ethyl acetate and washed with saturated brine. The organic layer was dried (over MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Biotage cartridge 40+M, ethyl acetate:n-hexane=15:85→1:4) to give methyl 5-benzyloxy-2-methoxybenzoate (3.72 g, 90%) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.[Cl-].[NH4+]>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:23][CH:24]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2C(C)(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(C(C)(C)C)n(Cc2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a solution of methyl 4-[(3,5-di-tert-butyl-1H-pyrazol-1-yl)methyl]benzoate (1.72 g, 5.24 mmol) in tetrahydrofuran (35 mL) was added lithium aluminum hydride (0.25 g, 5.3 mmol) at 0° C., and the mixture was stirred at room temperature for 30 min. Ethanol (10 mL) and saturated aqueous ammonium chloride solution (1.0 mL) were added to the reaction mixture, and the precipitated solid was filtered off. The filtrate was concentrated and the residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title compound (1.28 g, yield 81%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18](/[CH:24]=[CH:25]/[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: OCc1ccc(F)cc1/C=C/c1ccc(F)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)cc2/C=C/c2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.31 (2H, s), 5.82 (1H, d, J=1.6 Hz), 6.96-7.04 (4H, m), 7.22-7.23 (1H, m), 7.34-7.41 (5H, m), 7.59 (1H, d, J=1.6 Hz), 7.90 (1H, s), 8.51 (1H, d, J=4.8 Hz). [M+H] Calc'd for C24H16F2N4O, 415; Found, 415.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[C:12]([C:16]1[CH:31]=[CH:30][C:19]([C:20]([NH:22][C:23]2[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([NH:29][C:24]1[C:23]([NH:22][C:20](=[O:21])[C:19]2[CH:30]=[CH:31][C:16]([C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:17][CH:18]=2)=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:11]
Reactant: COc1cccc(C(=O)O)c1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1cccc(C(=O)Nc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 84.2 %

Procedure:
Using the procedure described in Example 102, Part A, 3-anisic acid (3.6 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (1.8 mmol) yielded 610 mg (84%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=3)[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccnc1
Reactant: COc1cccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Reaction time: 8 h
Yield: 68 %

Procedure:
7-Methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 4, 31.2 g, 57.7 mmol), nicotinic acid (10.7 g, 86 mmol) and diisopropylethylamine (30.1 mL, 173 mmol) were suspended in DMF (250 mL), and PyBOP (45 g, 86 mmol) was added portionwise. The reaction soon became much thicker with a new solid. After stirring overnight, the solid was collected by filtration then washed with EtOAc (150 mL). The solid was dissolved in CH2Cl2 (1000 mL), washed with water (600 mL) and the organic layer dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound (12.6 g, 68%): HPLC MS RT=1.18 min, MH+=322.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 4.12 (3H, s), 4.28-4.35 (2H, m), 4.60-4.66 (2H, m), 7.63 (1H, t), 7.72-7.86 (3H, m), 8.76 (1H, d), 8.93 (1H, dd), 9.48 (1H, d).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:12][C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)C(=O)OC(C)(C)C.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C.[CH3:36][O:37][C:38](=[O:44])[C@H:39]([CH:41]([CH3:43])[CH3:42])[NH2:40].O.O.O.C([O-])(=O)C.[Na+].[BH3-]C#N.[Na+]>ClCCl.CO.O>[CH3:42][CH:41]([CH3:43])[C@H:39]([NH:40][CH2:2][CH2:3][NH:4][CH2:12][C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)[C:38]([O:37][CH3:36])=[O:44]
Reactant: Cc1nc(CN(CCO)C(=O)OC(C)(C)C)cs1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NCCNCc1csc(C)n1)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of the product of Example 143B (2.26 g) in dichloromethane (20 mL) was treated with oxalyl chloride (5.4 mL, 1.5 equivalents) at −78° C., and stirred for 15 min. DMSO (1.02 mL, 2 equivalents) was added dropwise at −78° C., stirred for 15 min, and quenched with triethylamine (4 mL, 4 equivalents) as the mixture warmed to 0° C. The mixture was quenched with 20% KH2PO4, and partitioned between dichloromethane and water. The organic layer was washed with brine, dried over Na2SO4, filtered, and the solvents were evaporated. To this crude product was added methanol/water (7:2), (L)-valine methyl ester (1.21 g, 1 equivalent), sodium acetate trihydrate (1.96 g, 2 equivalents), and NaCNBH3 (0.95 g, 2 equivalents) was added portionwise over 30 min. After stirring for 1 hour the mixture was partitioned between saturated NaHCO3 and extracted with ethyl acetate (2×). The combined organic layer was washed with brine, dried with Na2SO4, and evaporated. The residue was treated with dichloromethane/trifluoacetic acid (10 mL, 1:1) and stirred at 25° C. for 2 hrs and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](OC2C=CC=CC=2)=[N:18][C:19]#[N:20])=[CH:12][CH:11]=1>C(#N)C>[C:19]([NH:18][C:17](=[N:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[O:16][C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)#[N:20]
Reactant: COc1cccc(N)c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: COc1cccc(N=C(NC#N)Oc2ccccc2)c1

Procedure:
m-Anisidine (4.56 mL, 4.06 mmol, 1 eq.), and diphenylcyanocarbonimidate (967 mg, 4.06 mmol, 1 eq.) were mixed and refluxed in acetonitrile under N2 for 1 hour. Solids precipitated. The reaction was worked up by filtering off the solids. Obtained 580 mg as product. M.P.=170.0-171.0° C. NMR (300 MHz, DMSO-d6) δ 8.70-8.50 (m, 1H); 7.43 (t, 2H, J 7 Hz); 7.40-7.20 (m, 2H); 7.14 (d, 2H, J=7 Hz); 7.00-6.80 (m, 2H); 6.80-6.70 (m, 1H); 3.80 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH:13]2[CH2:15][CH2:14]2)[CH:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:33]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)C(C)C)C.[OH-].[K+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH:13]2[CH2:15][CH2:14]2)[CH:10]([NH2:33])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C(C2CC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(N)C(C2CC2)C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
101.5 To a stirred solution of 200 mg (3RS,4RS)-4-cyclopropyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester at 80° C. in 2 ml dioxane under an argon atmosphere were added 0.20 ml diphenylphosphoryl azide and 0.16 ml N-ethyldiisopropylamine. Stirring at 80° C. was continued for 4 hrs. Then, the hot mixture was poured onto 15 ml 1 N KOH and the product was extracted with EtOAc. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 34 mg (3RS,4SR)-3-amino-4-cyclopropyl-pyrrolidine-1-carboxylic acid tert-butyl ester as light brown gum. MS 227.3 ([M+H]+)