Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:25](=[O:31])[CH2:26][CH2:27][C:28](O)=[O:29])[CH:10]=[CH2:11].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:28](=[O:29])[CH2:27][CH2:26][C:25]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:9][CH:10]=[CH2:11])=[O:31]
Reactant: O=C1CCC(=O)N1O
Reactant: C=CCOCCOCCOCCOCCOC(=O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=CCOCCOCCOCCOCCOC(=O)CCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
N-hydroxysuccin imide (1.58 g, 13.8 mmol) and succinic mono-(2-{2-[2-(2-allyloxy-ethoxy)-ethoxy]-ethoxy}-ethyl) ester (10) (4.6 g, 13.76 mmol) were dissolved in dry CH2Cl2 (10 mL) at room temperature. A solution of N,N′-dicyclohexylcarbodiimide (DCC) (2.84 g, 13.8 mmol) in dry CH2Cl2 (2 mL) was slowly added to the mixture at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The solid residues in the reaction mixture were filtered through a sintered glass filter and removed and the filtrate was concentrated to obtain the target compound in a yellow oily phase (5.5 g, 93%). The compound was used without further purification. The NMR analysis result of the product is as follows.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:16][C:17]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][C:20]1[N:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:26][C:23]4[CH:24]=[N:25][C:20]([O:19][C:18]5[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:17]=5[CH3:16])=[CH:21][CH:22]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Cc1cccc(Oc2ccc(N)cn2)c1C
Solvent: c1ccncc1
Product: Cc1cccc(Oc2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cn2)c1C
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 6-(2,3-dimethylphenoxy)pyridin-3-amine (43 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 402.4, found 403.1 (M+1)+. Retention time 3.11 minutes.
Reaction SMILES: [La:1].Cl.[C:3]([OH:8])(=[O:7])[C:4]([OH:6])=[O:5]>O>[C:3]([O-:8])(=[O:7])[C:4]([O-:6])=[O:5].[La+3:1].[C:3]([O-:8])(=[O:7])[C:4]([O-:6])=[O:5].[C:3]([O-:8])(=[O:7])[C:4]([O-:6])=[O:5].[La+3:1]
Reactant: O=C(O)C(=O)O
Reactant: [La]
Agent: Cl
Solvent: O
Product: O=C([O-])C(=O)[O-]
Product: [La+3]

Procedure:
The filtrate solution containing the twice-purified lanthanum was acidified, using 200 mL of hydrochloric acid (37.5% by weight). Then a stoichiometric amount of oxalic acid in 1000 mL water was slowly added to the heated lanthanum solution (approximately 70° C.), resulting in a lanthanum oxalate precipitate. The precipitate was recovered by filtering the suspension using a sintered glass crucible of coarse porosity. The precipitate was washed with 3 liters of distilled water, dried and then heated in air to convert it to 150 g of lanthanum oxide (85% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]([CH:16]=O)[CH3:15].C1C=CC2N(O)N=NC=2C=1.C[CH2:29][N:30]=[C:31]=NCCCN(C)C.Cl>O>[CH3:13][N:14]1[CH2:16][CH2:31][N:30]([C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:10])[CH2:29][CH2:15]1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.9 %

Procedure:
To a solution of 4-nitro-benzoic acid (10 g, 0.0598 mol) in DMF (300 mL) 1-methyl-piperazine (7.19 g, 0.0718 mol), HOBt (10.5 g, 0.0777 mol), EDC.HCl (17.12 g, 0.0897 mol) and TEA (12.1 g, 0.1196 mol) were added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×200 mL). The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford the title compound [14 g, 95%]; LC-MS (ESI): Calculated mass: 249.1; Observed mass: 250.0 [M+H]+ (RT: 0.10 min).
Reaction SMILES: Br[CH2:2][C:3]([CH2:5]Br)=O.[NH2:7][C:8]([NH2:10])=[S:9].Cl.[CH3:12][OH:13]>O>[CH3:12][O:13][CH2:2][C:3]1[N:7]=[C:8]([NH2:10])[S:9][CH:5]=1
Reactant: CO
Reactant: NC(N)=S
Reactant: O=C(CBr)CBr
Agent: Cl
Solvent: O
Product: COCc1csc(N)n1

Procedure:
1,3-Dibromoacetone (15 g, 52 mmol) and thiourea (4.05 g, 53.2 mmol, 1.02 equiv.) in methanol were refluxed overnight. The reaction mixture was diluted with water and the pH was adjusted to 1 with HCl 25%, followed by extraction with ethyl acetate. The pH of the aqueous layer was adjusted to 8-9 using solid sodium carbonate. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over magnesiumsulfat dihydrate, filtered and evaporated. The crude product was purified on silica-gel (NH2-modified) with ethyl acetate/n-heptane as eluent yielding a white solid: 340 mg. MS (ES) m/e 145 (M+H)
Reaction SMILES: [Br:1]C1C(C(OC)=O)=NC(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=CN=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:31]1[N:32]=[CH:33][C:34]([NH:39][C@@H:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][C@@H:41]2[OH:49])=[N:35][C:36]=1[O:37][CH3:38]>>[Br:1][C:33]1[C:34]([NH:39][C@@H:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][C@@H:41]2[OH:49])=[N:35][C:36]([O:37][CH3:38])=[C:31]([C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[Cl:23])[N:32]=1
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Reactant: COc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1-c1ccc(Cl)cc1Cl
Product: COc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(Br)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of methyl 3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate but substituting (1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxypyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 3.09-3.13, 3.29-3.34, 3.92, 4.81, 5.60-5.63, 5.99, 7.33-7.42, 7.49; MS (ESI+) for C20H16BrCl2N3O2 m/z 479 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17](O)=[O:18].[CH:20]([NH:23][NH:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:28][CH:27]=1)([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:28][CH:27]=1)=[O:18]
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Reactant: COCCOc1ccc(C(=O)NNC(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(=O)NN(C(=O)CCc2ccccc2-c2cccc(C)c2C)C(C)C)cc1
Yield: 15.3 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (110 mg, 0.44 mmoles) and 4-(2-methoxy-ethoxy)-benzoic acid-N′-isopropyl hydrazide (100 mg, 0.40 mmoles) in DMF (3 mL) was treated with triethylamine (0.16 mL, 1.19 mmoles), HOBT (64 mg, 0.48 mmoles) and EDCI (91 mg, 0.48 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with water, 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with 10% ethyl acetate/hexanes to afford the product (30 mg, 16%). LC-MS m/e 489.40 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([CH3:17])[CH:16]=1>>[CH3:9][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[C:15]([CH3:17])[CH:16]=[C:11]([CH3:10])[CH:12]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Cc1cc(C)cc(B(O)O)c1
Product: Cc1cc(C)cc(-c2cc(C)nc(N)n2)c1

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 2.0 g (14 mmol) 2-amino-4-chloro-6-methylpyrimidine and 2.7 g (18 mmol) 3,5-dimethyl-phenyl boronic acid. Yield after extraction and crystallization from diethylether: 3.2 g (75%, approximately 70% pure).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1.[F:36][C:37]1[CH:38]=[C:39]([NH:44][C:45]2[N:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[C:40]([NH2:43])=[CH:41][CH:42]=1>C(Cl)Cl.CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:11](=[O:13])[NH:43][C:40]1[CH:41]=[CH:42][C:37]([F:36])=[CH:38][C:39]=1[NH:44][C:45]1[N:46]=[CH:47][CH:48]=[CH:49][N:50]=1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(F)cc1Nc1ncccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ncccn1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
N-(tert-Butoxycarbonyl)-L-alanine (199 mg, 1.05 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (222 mg, 1.15 mmol) and HOAt (143 mg, 1.05 mmol) were added to 4-fluoro-N2-pyrimidin-2-yl-benzene-1,2-diamine (215 mg, 1.05 mmol) in DCM (8.0 ml) and DMF (800 μl) at 0° C. The reaction was stirred for 2 h then poured into water and the aqueous layer extracted with DCM (×3). The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by chromatography (SiO2, 0-10% methanol/DCM) to yield the title compound (350 mg, 0.93 mmol, 89%). LCMS: RT 2.98 min [M+H]+ 376.1. 1H NMR (CDCl3, 300 MHz): δ 8.48 (1H, br s), 8.42 (2H, d, J=4.9 Hz), 7.69 (1H, br s), 7.50 (2H, m), 6.84 (1H, td, J 8.5, 2.9 Hz), 6.76 (1H, t, J=4.9 Hz), 5.01 (1H, br s), 4.28 (1H, qn, J=7.6 Hz), 1.44 (9H, s), 1.43 (3H, d, J=7.4 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[S:68][C:67]([C:69]#[N:70])=[CH:66][CH:65]=1>>[C:69]([C:67]1[S:68][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)#[N:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)s1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)s2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 40.4 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.37 g, 1.6 mmol), then reacted with 5-amino-thiophene-2-carbonitrile prepared in Example 186 (0.11 g, 0.85 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-cyano-thiophen-2-yl)-amide as a white solid (Yield 0.12 g, 37%).
Reaction SMILES: [OH:1][CH:2]([CH2:5][OH:6])[CH2:3][NH2:4].[O:7]=[C:8]1[C:13]2[CH:14]=[CH:15]O[C:12]=2[CH2:11][CH2:10][CH2:9]1>C(O)C>[O:7]=[C:8]1[CH2:9][CH2:10][CH2:11][C:12]2[N:4]([CH2:3][CH:2]([OH:1])[CH2:5][OH:6])[CH:15]=[CH:14][C:13]1=2
Reactant: NCC(O)CO
Reactant: O=C1CCCc2occc21
Solvent: CCO
Product: O=C1CCCc2c1ccn2CC(O)CO
Temperature: 150 °C

Procedure:
9.4 g of 2,3-dihydroxypropylamine were added to a solution of 13.6 g of 4-oxo-4,5,6,7-tetrahydrobenzofuran in 200 cm3 of ethanol. The reaction medium was heated at 150° C. for 9 hours. After evaporation of the solvent and purification of the crude product on silica gel (ethyl acetate/methanol=9/1 ), 11.2 g of 4-oxo-4,5,6,7-tetrahydro-1-N-(β,γ-dihydroxypropyl)indole were recovered in the form of an oil.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc(F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1cc([N+](=O)[O-])cc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.2 %

Procedure:
To a solution of 2,3-difluorobenzaldehyde (2.9 g, 20.41 mmol) in conc. sulfuric acid (18 mL, 324 mmol) at 0° C., was added nitric acid (70%) (3.6 mL, 56.4 mmol) dropwise. The reaction mixture was removed from the ice bath and was stirred at rt for 3 h. The reaction mixture was poured onto ice, then was diluted to ˜350 mL with H2O. The aqueous was extracted with EtOAc (3×). The combined organic phase was washed with sat. NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was dissolved in EtOAc (10 mL), then was diluted with hexanes (40 mL). The solution was filtered though a 1″ pad of SiO2, then the pad was rinsed with 20% EtOAc/hexanes. The filtrate was concentrated. The resultant oil was dissolved in chloroform and hexanes, loaded onto a 150 g column and eluted with a gradient from 0 to 15% EtOAc/hexanes to give 11A (1.345 g, 7.19 mmol, 35.2% yield) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].N1C=CC=CC=1.O>C(Cl)Cl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Yield: 55.6 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (30.0 g) obtained from Referential Example 7 was dissolved in methylene chloride (300 ml), pivaloyl chloride (15.0 g) and pyridine (9.8 g) were added thereto, the mixture was refluxed for 2 hours and 30 minutes. The reaction mixture was allowed to cool, Water was added, and extracted with chloroform. The organic layer was successively washed with saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to thereby obtain the 21.5 g of titled compound as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[C:8]([CH3:22])[CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]4[CH:21]=3)=[C:8]([CH3:22])[CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1ccn2cc(-c3ccc(OCCCCl)cc3C)nc2c1
Reactant: C1CCNCC1
Product: Cc1ccn2cc(-c3ccc(OCCCN4CCCCC4)cc3C)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C (200 mg) and piperidine (2.0 mL) were heated at 100° C. for 2.5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with additional ethyl acetate (10 mL) and the organic portions combined, washed with brine, and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (110 mg). 1H-NMR (CD3OD) δ 8.28 (d, J=7.0 Hz, 1H), 7.78 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 6.79 (m, 2H), 4.04 (t, J=6.0 Hz, 2H), 2.50 (m, 12H), 1.99 (m, 2H), 1.64 (m, 4H), 1.51 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[Cl:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[C:29](=O)[CH2:28][CH2:27]2.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:29]3[C:30]4[C:26](=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:21])[CH2:27][CH2:28]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: O=C1CCc2cccc(Cl)c21
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CCc4cccc(Cl)c43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 7-chloro-indan-1-one using decaborane yielded a mixture of epimers of the title compound as a white foam. MS (ESI): m/z=429.3 [M+H]+.
Reaction SMILES: CO[CH:3]([O:6][CH3:7])[O:4][CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:19]([O-:22])([O-])=O.[Na+].[Na+].[CH3:25][OH:26]>>[CH3:7][O:6][C:3]([O:4][CH3:5])([CH2:19][OH:22])[CH2:25][OH:26]
Reactant: COC(OC)OC
Reactant: O=C([O-])[O-]
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Product: COC(CO)(CO)OC
Reaction time: 12 h
Yield: 47 %

Procedure:
2,2-dimethoxy-propane-1,3-diol (III) was synthesized according to the method of Ferroni, E. L., et al., J. Org. Chem., 64, 4943-4945 (1999). DHA dimer (25 g, 0.139 mole), trimethylorthoformate (30.4 ml, 0.278 mole) and p-toluenesulfonic acid (100 mg) were combined in 300 mL of methanol and stirred for 12 h. At this time 300 mg of Na2CO3 were added and the reaction mixture was stirred for an additional 12 h, after which the mixture was filtered and solvent was removed in vacuo. The resulting solid was recrystallized from ethyl ether to give 17.5 g of III (47%). 1H NMR (D2O) δ 3.58 (s; 4H), 3.24 (s; 6H). Anal. Calc.: C, 44.12; H, 8.82. Found: C, 44.50; H, 8.78.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([NH:18]C(=O)OC(C)(C)C)[C:15]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])=[CH:14][CH:13]=1)=O)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[NH2:18][C:16]1[C:15]([C:26](=[O:31])[C:27]([F:28])([F:30])[F:29])=[CH:14][CH:13]=[C:12]([NH:11][CH2:10][CH2:9][NH2:8])[N:17]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ccc(C(=O)C(F)(F)F)c(NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Reaction time: 20 h

Procedure:
2.5 g (5.57 mmol) of tert-butyl [6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-3-(trifluoroacetyl)-pyridin-2-yl]carbamate (Example 33A) were dissolved in 15 ml of a 4N solution of hydrogen chloride in dioxane, and the mixture was stirred for 20 h. The reaction mixture was concentrated to half of its original volume and the same amount of diethyl ether was added. The reaction mixture was stirred for 20 min and the product was filtered off and washed with diethyl ether. This gave 1.4 g (89% of theory) of the product as a solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[N:8]=[C:9]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][C:18]2=O)=[O:15])[NH:10][C:11]=1[CH2:12][CH3:13].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1.CO>[Cl:6][C:7]1[N:8]=[C:9]([C:14]([NH:16][C@@H:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][C@H:18]2[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:15])[NH:10][C:11]=1[CH2:12][CH3:13]
Reactant: C1CCNC1
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2N2CCCC2)nc1Cl
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Pyrrolidine (45 μL, 0.539 mmol) and 3 Å molecular sieves (100 mg) were added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (100 mg, 0.270 mmol) in tetrahydrofuran (3 mL), and the mixture was heated at 50° C. for four hours. Methanol (3 mL), pyrrolidine (45.0 μL, 0.539 mmol), sodium cyanoborohydride (51 mg, 0.809 mmol) and acetic acid (154 μL, 2.70 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain two isomers of the title compound, 21 mg of the cis isomer (18%) and 9 mg of the trans isomer (8%), as pale yellow oily substances.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[NH2:17][C:18]1[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=1>[Cu].O>[CH3:23][N:22]1[C:18]([NH:17][C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=[O:11])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: O=C(O)c1ccccc1I
Reactant: Cc1cc(N)n(C)n1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(Nc2ccccc2C(=O)O)n(C)n1

Procedure:
To a solution of 4.84 grams of potassium carbonate in 18 ml. of water were added in succession 8.0 grams of o-iodobenzoic acid, 3.88 grams of 5-amino-1,3-dimethyl pyrazole and 0.8 gram of the copper catalyst. The mixture was stirred at reflux for 5 hours. There was then added an additional 50 milliliters of water, the mixture being refluxed an additional 30 minutes and then filtered through diatomaceous earth. The filtrate was digested with decolorizing carbon, heated to reflux and filtered. The filtrate was cooled and acidified with 3N aqueous hydrochloric acid to produce N-(1,3-dimethyl-5-pyrazolyl)anthanilic acid, mp 175°-189° C., recrystallized from ethanol to give needles, mp 204°-206° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:14][C:15]1[C:16](Cl)=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>C1COCC1>[CH2:3]([N:10]1[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=2[O:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCN(Cc1ccccc1)Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2CCOc3ncccc3C2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
Under a nitrogen atmosphere, to a suspension of sodium hydride (60% in oil, 1.99 g) in THF (30 mL) was added a solution of the compound (6.90 g) obtained in step 2 in THF (20 mL) at 0° C., and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was cooled to 10° C., and poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 10→66% ethyl acetate/hexane) to give the title compound (4.51 g, 75%) as a pale-yellow oil.