Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:14]>C(O)(C)C>[Br:3][C:4]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[OH:14]
Reactant: O=C1CCc2c(Br)ccc(F)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OC1CCc2c(Br)ccc(F)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Reaction under argon atmosphere: to a mixture of 1.69 g (43.7 mmol) of sodium borohydride in 120 ml isopropyl alcohol is added 20.0 g (87.3 mmol) of 4-bromo-7-fluoro-1-indanone portionwise. The reaction mixture is stirred at r.t. for 2 h. The solvent is evaporated. To the residue are added 100 g ice and 200 ml 1N aq. HCl. The mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried and the solvent is evaporated. The residue is chromatographed on silica gel (PE/EtOAc=100/0→70/30) to give the title compound. Yield: 15.4 g; LC (method 4): tR=3.05 min; Mass spectrum (ESI+): m/z=213 [M+H—H2O]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Product: CCOC(=O)n1c(C(=O)c2cccc([N+](=O)[O-])c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-nitroacetophenone.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[O:18]=[C:19]1[C:27]2([C:31]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:30]=3[O:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1>>[O:18]=[C:19]1[C:27]2([C:31]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:30]=3[O:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: N#Cc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Product: N#Cc1ccc2c(c1)OCC21C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile was obtained (89%) as a colorless solid: mp 151-153° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J=3.9 Hz, 1H), 7.66 (t, J=7.5 Hz, 1H), 7.34-6.84 (m, 9H), 5.19 (d, J=15.8 Hz, 1H), 5.07 (d, J=9.2 Hz, 1H), 4.97 (d, J=15.8 Hz, 1H), 4.79 (d, J=9.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.3, 160.7, 155.1, 149.7, 142.3, 137.1, 134.8, 131.2, 129.5, 125.8, 124.6, 123.8, 122.9, 121.8, 118.5, 113.8, 113.3, 109.9, 80.21, 77.5, 57.9, 46.1; MS (ES+) m/z 353.9 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12](=[O:14])(=[O:13])[CH:11]=[CH:10][C:9]=2[CH:15]=1)=[O:4].Cl.[C@@H:17]12[N:24]([CH2:25][C@@H:26]([C:28]3[C:29]([CH3:38])=[C:30]4[C:34](=[CH:35][CH:36]=3)[C:33](=[O:37])[O:32][CH2:31]4)[OH:27])[C@@H:21](CC1)[CH2:20][NH:19][CH2:18]2.C(N(CC)C(C)C)(C)C>C1COCC1>[O:13]=[S:12]1(=[O:14])[C:8]2[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH2:2][N:19]3[CH2:18][CH2:17][N:24]([CH2:25][C@@H:26]([C:28]4[CH:36]=[CH:35][C:34]5[C:33](=[O:37])[O:32][CH2:31][C:30]=5[C:29]=4[CH3:38])[OH:27])[CH2:21][CH2:20]3)=[CH:15][C:9]=2[CH:10]=[CH:11]1
Reactant: O=C(CBr)c1ccc2c(c1)C=CS2(=O)=O
Reactant: Cc1c([C@@H](O)CN2[C@@H]3CC[C@H]2CNC3)ccc2c1COC2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c([C@@H](O)CN2CCN(CC(=O)c3ccc4c(c3)C=CS4(=O)=O)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-1-(1,1-dioxido-1-benzothiophen-5-yl)ethanone (50 mg, 0.17 mmol) in 1.0 mL THF and 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride (INTERMEDIATE 12) (61 mg, 0.17 mmol) was added N,N-diisopropylethylamine (0.70 mmol, 120 μL) and allowed to stir at ambient temperature for 2 hours. The reaction was quenched by the addition of water and extracted three times with ethyl acetate (10 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified via MPLC (10% DCM/MeOH) to afford 5-[(1R)-2-{4-[2-(1,1-dioxido-1-benzothiophen-5-yl)-2-oxoethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1 (3H)-one.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([NH:8]C(=O)OCC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([CH2:19][CH:20]2[C:24]3=[C:25]([F:33])[CH:26]=[N:27][C:28]4[CH:29]=[CH:30][C:31](=[O:32])[N:22]([C:23]=43)[CH2:21]2)[CH2:3]1.O1CCOCC1>C(O)C.[Pd]>[NH2:8][C@H:7]1[CH2:6][CH2:5][N:4]([CH2:19][CH:20]2[C:24]3=[C:25]([F:33])[CH:26]=[N:27][C:28]4[CH:29]=[CH:30][C:31](=[O:32])[N:22]([C:23]=43)[CH2:21]2)[CH2:3][C@H:2]1[F:1]
Reactant: O=C(N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@H]1F)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@H]1F
Reaction time: 5 h
Yield: 86.8 %

Procedure:
A solution of racemic phenylmethyl {cis-3-fluoro-1-[(3-fluoro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-piperidinyl}carbamate (1.218 g) in ethanol (20 ml)/1,4-dioxane (5 ml) was treated with 10% Pd/C (600 mg) and stirred under hydrogen at atmospheric pressure for 5 hours. After filtration through kieselguhr, the filtrate was evaporated and the residue chromatographed on silica gel, eluting with dichloromethane/methanol/0.88 aqueous ammonia, to give the desired compound (745 mg, 86%).
Reaction SMILES: NC1N=CC(N2CCN(C(OC(C)(C)C)=O)CC2)=CC=1.[N+:21]([C:24]1[N:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)([O-])=O>>[O:33]1[CH2:34][CH2:35][N:30]([C:27]2[CH:26]=[CH:25][C:24]([NH2:21])=[N:29][CH:28]=2)[CH2:31][CH2:32]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cn1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Product: Nc1ccc(N2CCOCC2)cn1

Procedure:
Following the procedures as described for 188b and starting with 1 g of 4-(6-nitropyridin-3-yl)morpholine, 255b was obtained as a yellow solid (840 mg, 98%). MS: [M+H]+ 210
Reaction SMILES: [CH2:1]([C:3]1([CH2:6][CH3:7])[CH2:5][O:4]1)[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH:12]=[CH:13][CH:14]=1>>[CH2:1]([C:3]([OH:4])([CH2:6][CH3:7])[CH2:5][NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: Nc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: CCC1(CC)CO1
Product: CCC(O)(CC)CNc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Reaction between 2,2-diethyloxirane and 2-(3-(3-aminophenyl)propyl)isoindoline-1,3-dione gives 2-(3-(3-((2-ethyl-2-hydroxybutyl)amino)phenyl)propyl)isoindoline-1,3-dione.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[CH3:11][N:12]([CH3:32])[CH2:13][CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:18][C:17]1=[O:31]>>[CH3:11][N:12]([CH3:32])[CH2:13][CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[C:1]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH3:3])=[CH:18][C:17]1=[O:31]
Reactant: CN(C)CCCn1ccc(C(=O)c2ccc(O)cc2)cc1=O
Reactant: CCC(=O)c1ccccc1
Product: CCC(=C(c1ccc(O)cc1)c1ccn(CCCN(C)C)c(=O)c1)c1ccccc1

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, propiophenone (0.838 g, 3.0 eq) was reacted with 1-(3-(dimethylamino) propyl)-4-(4-hydroxybenzoyl)pyridin-2(1H)-one (0.8 g, 1.0 eq) to give the desired product (Z was prepared by preparative HPLC). 1H NMR (400 MHz, DMSO-d6) δ 9.54 (brs, 1H), 7.34 (d, J=6.8 Hz, 1H), 7.17-7.29 (m, 5H), 7.04 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.4 Hz, 2H), 5.83 (d, J=1.6 Hz, 1H), 5.75 (dd, J=6.8 Hz, 1.6 Hz, 1H), 3.75 (t, J=6.8 Hz, 2H), 2.93 (t, J=6.8 Hz, 2H), 2.73 (s, 6H), 2.37 (q, J=7.2 Hz, 2H), 1.86-1.90 (m, 2H), 0.83 (t, J=7.2 Hz, 3H); m/z=403[M+1]+.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][C@@H:28]1[S:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]1)[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([O:18][C:19]([NH:21][C@H:22]([C:23]([O:25][CH2:2][C:1]#[N:4])=[O:24])[CH2:26][CH2:27][C@@H:28]1[S:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC[C@H]1CN(C(=O)OC(C)(C)C)CS1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC[C@H]1CN(C(=O)OC(C)(C)C)CS1)C(=O)OCC#N
Reaction time: 3 h
Yield: 87.2 %

Procedure:
N,N-Diisopropylethylamine (48 μL, 0.276 mmol) and subsequently bromoacetonitrile (88 μL, 1.255 mmol) were added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-4-((S)-3-(tert-butoxycarbonyl) thiazolidin-5-yl)butanoic acid (Compound tk2) (98 mg, 0.251 mmol) in acetonitrile (0.5 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 3 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-tert-butyl 5-((S)-3-((tert-butoxycarbonyl)amino)-4-(cyanomethoxy)-4-oxobutyl)thiazolidine-3-carboxylate (Compound tk3) (94.0 mg, 87%).
Reaction SMILES: [CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]([O:12]C(=O)C)[C@H:10]1[NH:28][C:29]([C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41]([NH:43][C@@H:44]3[C@@H:50]([O:51]C(=O)C)[C@H:49]([O:55]C(=O)C)[C@@H:48]([CH2:59][O:60]C(=O)C)[O:47][C@:45]3([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[OH:46])=[O:42])[CH:37]=2)[CH:32]=1)=[O:30])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO.O1CCOCC1>[CH2:64]([C@@:45]1([O:47][C@H:48]([CH2:59][OH:60])[C@@H:49]([OH:55])[C@H:50]([OH:51])[C@H:44]1[NH:43][C:41]([C:36]1[CH:35]=[CH:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([C:29]([NH:28][C@@H:10]3[C@@H:11]([OH:12])[C@H:16]([OH:17])[C@@H:21]([CH2:23][OH:24])[O:22][C@:8]3([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[OH:9])=[O:30])[CH:32]=2)[CH:37]=1)=[O:42])[OH:46])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: CC(=O)OC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](NC(=O)c2ccc3cc(C(=O)N[C@@H]4[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@]4(O)Cc4ccccc4)ccc3c2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@]1(O)Cc1ccccc1)c1ccc2cc(C(=O)N[C@@H]3[C@@H](O)[C@H](O)[C@@H](CO)O[C@@]3(O)Cc3ccccc3)ccc2c1

Procedure:
A solution of 1.0 g of (naphthalene-2,6-dicarboxylic acid bis- [(benzyl 3,4,6-tri-O-acetyl-2-desoxy-α-D-glucopyranosid-2-yl)-amide] in 20 ml of methanol and 20 ml of dioxan was stirred at room temperature for 18 hours with ml of a 0.3M sodium methanolate solution. The resulting precipitate was washed with methanol, dioxan and ether, dried and gave naphthalene-2,6-dicarboxylic acid bis-[(benzyl 2-desoxy-α-D-glucopyranosid-2-yl)-amide], MS: m/z 717.2 ([M-H]-).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:15])[C:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[N:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH3:15])[C:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[N:8][CH:9]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1CCCC#N
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cnc1CCCC#N
Yield: 93.3 %

Procedure:
5-Nitro-2-(3-cyanopropyl)-3-methylpyridine (5.9 g) was hydrogenated in ethanol (150 ml) with palladium on charcoal (0.59 g of 10%) at 140 kPa, for 2.5 hrs. The filtered solution was concentrated to dryness, the residue was triturated with ether to give 5-amino-2-(3-cyanopropyl)-3-methylpyridine (4.70 g) m.p. 103°-105° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:38]=[CH:37][C:12]([O:13][CH2:14][C:15]([O:24][C:25]3[C:34]([CH3:35])=[C:33]4[C:28]([C:29](=[O:36])[CH2:30][CH2:31][O:32]4)=[CH:27][CH:26]=3)([CH3:23])[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:11][CH:10]=2)[S:3]1.Cl>O1CCOCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:38]=[CH:37][C:12]([O:13][CH2:14][C:15]([O:24][C:25]3[C:34]([CH3:35])=[C:33]4[C:28]([C:29](=[O:36])[CH2:30][CH2:31][O:32]4)=[CH:27][CH:26]=3)([CH3:23])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)[S:3]1
Reactant: Cc1c(OC(C)(COc2ccc(CC3SC(=O)NC3=O)cc2)C(=O)OC(C)(C)C)ccc2c1OCCC2=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(OC(C)(COc2ccc(CC3SC(=O)NC3=O)cc2)C(=O)O)ccc2c1OCCC2=O
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A mixture of 100 mg of t-butyl 2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,8-dimethyl-4-oxochroman-7-yloxyacetate (prepared as described in Example 12) and 2 ml of a 4N solution of hydrogen chloride in dioxane was allowed to stand overnight at room temperature. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure. The resulting residue was washed with water, to afford 84 mg of the title compound as a pale orange powder, softening at 176°-179° C.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([Br:13])=[CH:8][N:7]=1.[OH-:14].[Na+]>O.S(=O)(=O)(O)O>[Br:13][C:9]1[CH:8]=[N:7][C:6]([OH:14])=[CH:11][C:10]=1[CH3:12]
Reactant: Cc1cc(N)ncc1Br
Reactant: [OH-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)ncc1Br
Temperature: 0 °C
Yield: 31 %

Procedure:
Sodium nitrite (5.44 g, 78.8 mmol) in water (14 ml) was added dropwise to 2-amino-5-bromo-4-methylpyridine (12.83 g, 68.6 mmol) in sulphuric acid (20%) (69 ml) at 0-5° C. After 1 h at 0° C. the solution was heated to reflux for 1 h. The solution was basified to pH 10 with sodium hydroxide solution (40%) and cooled to 5° C. and the precipitated product separated by filtration. Recrystallisation from ethanol gave the title compound (5.97 g, 31%) as white needles (m.p.200°-201° C.); δH (D6 -DMSO) 2.17 (3H, s, CH3), 6.40 (1H, s, 3-H), 7.76 (1H, s, 6-H), 11.58 (1H, s, NH): m/z (E.I.) 189 (M+, 100%), 187 (M+, 97%); (Found: M+, 186.9634. C6H6NOBr requires M, 186.9633).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH2:13][N:12]([CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:11]([C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[CH2:10]2)[CH:2]=[CH2:3].[C:41](=O)([O-])[O-:42].[K+].[K+].C(Br)C=C.C(OCC)(=O)C>CN(C=O)C>[F:38][C:33]1[CH:32]=[C:31]([CH:36]=[C:35]([F:37])[CH:34]=1)[CH2:30][C@H:29]1[C@@H:28]([C@H:11]2[CH2:10][C:9]3[C:14](=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:6]=[CH:7][CH:8]=3)[CH2:13][N:12]2[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:40][C:41](=[O:42])[NH:39]1
Reactant: O=C([O-])[O-]
Reactant: C=CCOc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)C2
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: C=CCOc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-2-benzhydryl-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one (Step F (14), 40 mg, 0.076 mmol) in DMF (2 mL) were added potassium carbonate (52 mg, 0.38 mmol) and allyl bromide (73 mg, 0.61 mmol). The mixture was stirred at rt overnight. Ethyl acetate (100 mL) was added and the mixture was washed with H2O (70 mL) twice, and dried over Na2SO4, and concentrated under vacuum to give the title compound: 1H NMR (CDCl3, 500 MHz) δ 2.50 (1H, m), 2.76 (1H, d, J=15 Hz), 2.90 (1H, d, J=35 Hz), 3.19 (1H, m), 3.26 (1H, dd, J=5, 10 Hz), 3.75 (1H, d, J=20 Hz), 3.80 (1H, m), 4.00 (1H, m), 4.13 (1H, d, J=20 Hz), 4.40 (2H, m), 4.72 (1H, dd, J=5, 10 Hz), 4.83 (1H, s), 4.87 (1H, s), 5.12-5.17 (2H, m), 5.84 (1H, m), 6.65 (1H, d, J=10 Hz), 6.75-6.80 (4H, m), 7.13-7.16 (1H, m), 7.19-7.32 (6H, m), 7.36 (2H, d, J=5 Hz), 7.42 (2H, d, J=5 Hz). MS (ESI) (M+H)+ 567.19.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]([C:19]3[CH2:23][C:22]4([CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][N:20]=3)=[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[CH:5]=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:34]1(Br)[CH2:38][CH2:37][CH2:36][CH2:35]1>C(#N)C>[CH:34]1([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:11]3[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=4[N:8]=[CH:9][C:10]=3[C:19]3[CH2:23][C:22]4([CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][N:20]=3)[CH2:18][CH2:17]2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: BrC1CCCC1
Reactant: CCn1ncc2c(NC3CCNCC3)c(C3=NOC4(CCCC4)C3)cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1ncc2c(NC3CCN(C4CCCC4)CC3)c(C3=NOC4(CCCC4)C3)cnc21

Procedure:
1-Ethyl-5-(1-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-piperidin-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine (70 mg, 0.0018 mole) (example 31) was taken in acetonitrile and potassium carbonate (126 mg, 0.0009 mole) and cyclopentyl bromide (0.020 ml, 0.0002 mole) were added. The reaction mixture was stirred at refluxing temperature overnight. Acetonitrile was removed and water was added to the residue. Extraction was done with ethyl acetate and washings were done with brine. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure and the crude product was purified by preparative thin layer chromatography.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[C:22]([F:39])=[C:23]([C@H:28]([NH:31]C(=O)OC(C)(C)C)[CH2:29][CH3:30])[CH:24]=[CH:25][C:26]=2[Cl:27])=[O:20])=[CH:15][CH:14]=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:31][CH:28]([C:23]1[C:22]([F:39])=[C:21]([C:19]([C:16]2[CH:15]=[CH:14][C:13]([OH:12])=[CH:18][CH:17]=2)=[O:20])[C:26]([Cl:27])=[CH:25][CH:24]=1)[CH2:29][CH3:30]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(OCc3ccccc3)cc2)c1F
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(N)c1ccc(Cl)c(C(=O)c2ccc(O)cc2)c1F
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
Step 3 Boron trichloride (1M in dichloromethane, 10 ml) was added to a solution of tert-butyl N-[(1R)-1-(3-{[4-(benzyloxy)phenyl]carbonyl}-4-chloro-2-fluorophenyl)propyl]carbamate (1.53 g, 3.07 mmol) in dichloromethane (50 ml) in an ice/water bath. The mixture was stirred for 30 minutes then the reaction mixture was poured onto ice/water. The aqueous was basified with saturated sodium bicarbonate and then extracted with dichloromethane (×2). The organic liquors were concentrated and then treated with 2N hydrochloric acid in ethyl acetate to remove protecting group. The residue was concentrated and re-concentrated from ethyl acetate. A solid was obtained from ethyl acetate/diethyl ether mixtures which was isolated by filtration and dried in a vacuum oven to furnish the title compound as an off-white solid (481 mg).
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:4]=[C:5]([C:13]([O-])=[CH:14][C:15](=O)[C:16]([O:18]CC)=[O:17])[CH:6]=[C:7]([O:9][CH:10]([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([NH:52][NH2:53])[CH:47]=1>>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[N:52]([C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)[N:53]=[C:15]([C:16]([OH:18])=[O:17])[CH:14]=2)[CH:6]=[C:7]([O:9][CH:10]([F:11])[F:12])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Cl)cc(OC(F)F)c1
Reactant: NNc1cccnc1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Cl)cc(OC(F)F)c2)n(-c2cccnc2)n1

Procedure:
350 mg (0.80 mmol) of the compound of Example 8A is reacted analogously to the synthesis of the compound of Example 20A with 128 mg (0.88 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 176 mg (60% of theory) of the title compound is obtained.
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]=[CH:4][I:5].N1C=CN=C1.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19].CCCCCC>CN(C)C=O>[I:5][CH:4]=[CH:3][C:2]([CH3:11])([O:1][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC(C)(O)C=CI
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCCCC(C)(C=CI)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a stirred solution of 11.7 g of 3-hydroxy-1-iodo-3-methyl-1-octene Example 184) and 7.4 g of imidazole in 45 ml of dry dimethylformamide is added dropwise 5.98 g of trimethylsilylchloride at 0° C. under argon atmosphere. After stirring at 0° C. for an additional 15 minutes, the solution is stirred at ambient temperature for 18 hours. The reaction mixture is poured into 600 ml of hexane and the resulting solution washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and taken to dryness to furnish 14.7 g of oil. Distillation affords 13.4 g of clear oil; bp 65° C. (0.05 mm); λ max 6.21, 8.00, 9.90, 10.51, 11.90, 13.2μ.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([O:19]CC)=O)[N:14]=[N:13]2)=[C:8]([OH:22])[CH:7]=1)=[O:5])[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(N(CC)CC)C>[CH:23]1([NH:26][C:17]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][C:8]=3[OH:22])[CH:16]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)OCC)nn2)c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
The product obtained in the same manner as in Example 133e) from ethyl 1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-1H-1,2,3-triazole-4-carboxylate (2.37 g) obtained in Example 133c) was dissolved in DMF (18 ml), cyclopropylamine (0.51 ml), triethylamine (1.01 ml), HOBt (1.12 g) and WSC (1.40 g) were successively added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was acidified with 1N hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to give the title compound as a pale-brown powder (1.41 g, yield in 2 steps 59%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[NH2:16])=[CH:4][CH:3]=1.C([C:19]1[C:20]([N:28]=[CH:29][N:30]([CH3:32])C)=[N:21][C:22]([CH:25]2[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)#N.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH:25]1([C:22]2[CH:23]=[CH:24][C:19]3[C:32]([NH:16][C:10]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=4[S:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:30][CH:29]=[N:28][C:20]=3[N:21]=2)[CH2:26][CH2:27]1
Reactant: CN(C)C=Nc1nc(C2CC2)ccc1C#N
Reactant: Cc1ccc(Sc2ccc(F)cc2)c(N)c1
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: Cc1ccc(Sc2ccc(F)cc2)c(Nc2ncnc3nc(C4CC4)ccc23)c1

Procedure:
2-(4-Fluoro-phenylsulfanyl)-5-methyl-phenylamine was reacted with the product from Example 119A using the procedure from Example 102 substituting 2-(4-Fluoro-phenylsulfanyl)-5-methyl-phenylamine for the product from Example 6c and substituting the product from Example 119A for the product from Example 10B to provide the crude residue which was purified by trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.96-1.19 (m, J=6.25 Hz, 4H), 2.22-2.42 (m, 1H), 2.33 (s, 3H), 7.02-7.28 (m, 6H), 7.33 (s, 1H), 7.56 (d, J=8.46 Hz, 1H), 8.46 (s, 1H), 8.66 (d, J=8.09 Hz, 1H), 10.03 (s, 1H); MS (ESI)+ m/z 403 (M+H)+.