Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:31]=[CH:30][C:23]([C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])=[C:22]([F:32])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:34][OH:35].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:31]=[CH:30][C:23]([C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])=[C:22]([F:32])[CH:21]=1)[CH2:9]/[C:10](=[N:34]\[OH:35])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NC3CC3)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NC3CC3)c(F)c2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N-cyclopropyl-2-fluorobenzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 4% of the corresponding Z isomer as a colorless waxy solid, MS (ESI+): m/z=468.2 [M+H]+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][N:4]1[C@@H:21]2[CH2:22][C:9]3[CH:10]=[CH:11][C:12]([OH:24])=[C:13]4[O:14][C@H:15]5[C:16]([CH2:18][CH2:19][C@:20]2([OH:23])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=O.Cl.Cl.C[O:28][NH2:29].[OH-].[Na+].[CH3:32]O>O>[CH3:32][CH:16]1[C:18](=[N:29][OH:28])[CH2:19][C@:20]2([OH:23])[C@:7]34[CH2:6][CH2:5][N:4]([CH2:3][CH:2]=[CH2:1])[C@@H:21]2[CH2:22][C:9]2[CH:10]=[CH:11][C:12]([OH:24])=[C:13]([O:14][C@@H:15]13)[C:8]4=2
Reactant: CO
Reactant: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(C)C(=NO)C[C@@]3(O)[C@H]1C5

Procedure:
A solution of naloxone hydrochloride (1.09 g, 3 mmol) and O-methylhydroxylamine hydrochloride (0.33 g, 3.9 mmol) in 15 mL MeOH was stirred overnight. After the addition of 3.2 mL of 10% aqueous NaOH, the mixture was refluxed for 5 h. It was cooled, diluted with approx. 100 mL of water, and extracted with 150 mL CHCl3 (3×50 mL). The combined extracts were dried (MgSO4) and evaporated. The residue obtained was recrystallized from hexane-petroleum ether. Yield 0.8 g, (75%) mp 128°-129° C. IR (KBr): No C=O absorption at 1717 cm-1. 1H NMR (CDCl3): δ 4.95 (s, C5H), 3.82 (s, OCH3). Rf: silica gel 60 in EtOAc--EtOH--NH4OH (100:1:1) 0.50. Anal. Calcd for C20H24N2O4C, 67.40; H, 6.79; N, 7.86. Found: C, 67.27; H, 6.84; N, 7.82.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][C:31]([NH2:34])([CH3:33])[CH3:32].N1C2C(=CC=CC=2)C(CC(N)(C)C)=C1>>[ClH:20].[NH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[CH:29][CH:28]=2)[C:24]([CH2:30][C:31]([NH:34][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([CH3:18])[CH3:19])([CH3:32])[CH3:33])=[CH:25]1
Reactant: CC(C)COc1ccccc1OCCOS(C)(=O)=O
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Agent: CC(C)(N)Cc1c[nH]c2ccccc12
Product: CC(C)COc1ccccc1OCCNC(C)(C)Cc1c[nH]c2ccccc12
Product: Cl

Procedure:
Proceeding as an Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-[2-(2-methylprop-1-yloxy)phenoxy]ethyl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2- (1H-indol-3-yl)-1,1-dimethylethyl]amine, gave [2-(1H-indol-3-yl)-1,1-dimethylethyl]{-[2-(2-methylprop-1-yloxy)phenoxy]ethyl}amine hydrochloride, m.p. 147°-148° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=2)[CH2:4][CH2:3]1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[C:47]1([C:53]2[CH2:54][CH2:55][N:56]([CH2:59][CH2:60][CH2:61][CH2:62][NH2:63])[CH2:57][CH:58]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.Cl>O.C(N(CC)CC)C.CN(C)C=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:63][CH2:62][CH2:61][CH2:60][CH2:59][N:56]3[CH2:55][CH:54]=[C:53]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:58][CH2:57]3)=[O:15])=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: NCCCCN1CC=C(c2ccccc2)CC1
Reactant: CN1CCN(Cc2ccc(C(=O)O)c([N+](=O)[O-])c2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(C(=O)NCCCCN3CC=C(c4ccccc4)CC3)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 4-(4-methylpiperazin-1-ylmethyl)-2-nitrobenzoic acid (0.28 g), hydroxybenzotriazole (0.14 g) and dry dimethylformamide (5 ml) was added dicyclohexylcarbodiimide (0.21 g), and the mixture was stirred for 1 hour at room temperature. Then 4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butylamine hydrochloride (0.27 g) and triethylamine (0.20 g) were added and the stirring was continued for additional 1 hour. 1N Hydrochloric acid (2 ml) and water (20 ml) were added and the mixture was washed with ethyl acetate, adjusted to pH 8 with aqueous sodium bicarbonate solution and extracted with ethyl acetate (x2). The combined organic extracts were dried over magnesium sulfate and solvent was evaporated to give 4-(4-methylpiprazin-1-ylmethyl)-2-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide (0.21).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:19])[N:4]([CH3:18])[C:5]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[C:6]2[C:11]=1[C:10](=O)[NH:9][CH2:8][CH2:7]2.[C:20]([O-:23])([O-])=O.[Cs+].[Cs+].[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:30]Br.[H-].[Na+]>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:10][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([O:1][CH2:30][C:29]3[CH:32]=[CH:33][C:34]([F:35])=[C:27]([Cl:26])[CH:28]=3)[C:3](=[O:19])[N:4]([CH3:18])[C:5]=2[C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[C:20]1=[O:23]
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: O=C([O-])[O-]
Reactant: CN(C)C(=O)c1c2c(c(O)c(=O)n1C)C(=O)NCC2
Agent: [Cs+]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1c2c(c(OCc3ccc(F)c(Cl)c3)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 40 °C

Procedure:
A solution of 4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (0.018 g, 0.068 mmol) in DMF (2 mL) was treated with Cs2CO3 (0.066 g, 0.2 mmol) and 3-chloro-4-fluoro benzyl bromide (0.045 g, 0.2 mmol) and heated to 40° C. The reaction mixture was then cooled to 0 degrees C., a suspension of NaH (95% dispersion in oil, 0.2 mmol) was added and the reaction was warmed to room temperature. After 1 hr the reaction was partitioned between ice water and EtOAc, the organic layer was dried with brine and Na2SO4, filtered and evaporated to give 6-(3-chloro-4-fluorobenzyl)4-[(3-chloro-4-fluorobenzyl)oxy]-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (ES MS M+1=549.9). This material was then dissolved in CH2Cl2 (3 mL) and treated with 4 drops of a 30% by weight solution of HBr in propionic acid at room temperature. After 20 minutes the solution was concentrated and purified by reverse phase chromatography to give the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([C:36]([F:39])([F:38])[F:37])[CH:28]=1)[CH3:25]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:29]([C:36]([F:37])([F:38])[F:39])[CH:28]=1)[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: CCOc1ccc(B(O)O)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: CCOc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
Tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) was dissolved in DME (7.8 mL). Ba(OH)2 8H2O (236.6 mg, 0.75 mmol) in H2O (2.6 mL) was added. 4-ethoxy-2-trifluoromethylphenyl boronic acid (140 mg, 0.6 mmol) was added followed by Pd(PPh3)4 (12 mg, 0.01 mmol). The reaction flask was degassed and refluxed under a nitrogen atmosphere for 18 hrs. After cooling to RT, the reaction was concentrated in vacuo. Water (10 mL) and EtOAc (10 mL) were added. The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine (2×10 mL), dried over MgSO4 and concentrated in vacuo and after chromatographic purification (30% EtOAc/Hexane) to afford the title compound (140 mg, 57%). 1H NMR (CDCl3, 300 MHz) δ 7.20 (d, 2H, J=5.9 Hz), 7.19 (s, 1H), 7.01 (dd, 1H, J=6.2, 2.2 Hz), 6.85 (s, 1H), 6.81 (s, 1H), 4.05-4.10 (m, 3H), 3.82-3.94 (m, 1H), 3.64-3.68 (m, 1H), 3.22-3.44 (m, 4H), 2.84-3.10 (m, 3H), 1.80-1.90 (m, 2H), 1.42-1.47 (m, 12H) ppm. MS-ApCI: 489 [M+H+].
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>ClCCl>[CH:14]1([N:10]2[CH2:11][CH2:12][CH2:13][N:7]([C:5]([CH:3]3[CH2:2][N:1]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:4]3)=[O:6])[CH2:8][CH2:9]2)[CH2:17][CH2:16][CH2:15]1
Reactant: CCC(=O)Cl
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 11.6 %

Procedure:
To a stirred solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (125 mg, 0.53 mmol) in dichloromethane (5 ml) at 0° C. was added sodium carbonate (167 mg, 1.58 mmol) and propionyl chloride (58 mg, 0.63 mmol). The resulting mixture was stirred at RT for 13 h before volatiles were removed under reduced pressure. Purification by silica FCC (using a gradient of eluents; 100:0 to 98:2 DCM:2M NH3 in MeOH) followed by purification by preparative HPLC (Method 2) gave the title compound (18 mg, 12% yield) as pale yellow oil. LCMS data: Calculated MH1(294). Found 86% (MH1) m/z 294, Rt=3.18 min (Method D).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[CH:9][CH:10]=[C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=O)[C:4]([O:6]CC)=S.F[B-](F)(F)F.CN(C)C(C(=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=CC=[N+](C)C.CC[O-].[Na+].C1([S:56]CC(OCC)=O)C=CC=CC=1>C(O)C>[CH3:23][N:2]([CH3:1])[C:3]([C:4](=[O:6])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[CH:9][CH:10]=[C:11]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:12]([O:14][CH2:15][CH3:16])=[S:56]
Reactant: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Reactant: CN(C)C(=CC=[N+](C)C)C(=O)c1ccccc1
Reactant: CCOC(=O)CSc1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCO
Product: CCOC(=S)C(=CC=C(C(=O)c1ccccc1)N(C)C)c1ccccc1

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-benzoylpropenylidene)-N-methylmethanaminium tetrafluoroborate (5 g), a 2M ethanolic solution of sodium ethylate (7.9 cc) and ethyl (phenylthio)acetate (3.1 g) in ethanol (50 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (80:20 by volume) as eluent, ethyl 5-dimethylamino-5-benzoyl-2-phenylthio-2,4-pentadienoate (4.1 g), m.p. 58° C., is obtained.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]([OH:24])[CH:22]=[CH2:23])[CH:18]=[CH:19][CH:20]=1>>[C:4]([Si:1]([O:24][CH:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=1)[CH:22]=[CH2:23])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C=CC(O)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: C=CC(O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 22.4 g (133 mmol) of 1-(3-chlorophenyl)prop-2-en-1-ol in 90 mL anhydrous DMF (from Step A) was added t-butyldimethylsilyl chloride (20.0 g, 133 mmol) and imidazole (18.1 g, 266 mmol) and the resulting solution was stirred overnight under nitrogen at room temperature. Wash with water and extract with ethyl acetate. Separate organics, dry over magnesium sulfate, filter, and concentrate under vacuum. The residue was purified by flash silica gel column eluting with a gradient eluent of 0-15% ethyl acetate in hexane to afford the title compound (16.6 g, 46%). m/z (ES) 282, 284 (M, M+2)+; 151, 153 (M-OTBS, M-OTBS+2)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[OH-].[Na+].[O-:14][C:15]#[N:16].[Na+].C(O)(=O)C>O.O1CCOCC1>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:15]([OH:14])[N:16]=[C:4]2[OH:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: N#C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: Oc1nc(O)c2cc(I)ccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of commercially available 2-amino-5-iodobenzoic acid (1 g, 3.80 mmol) in water (5 mL) and 2N aqueous sodium hydroxide (1.9 mL, 3.80 mmol), was added sodium cyanate (272 mg, 4.18 mmol). The reaction mixture was then diluted with dioxane (3 mL). The reaction mixture was maintained at approximate pH 6–7 over the course of 3 hours, by the addition of acetic acid (228 μl). The mixture was stirred at room temperature for 18 hours then cooled to 0 C. The pH of the reaction was adjusted to 13–14 with the addition of 6N aqueous sodium hydroxide (1 mL), then the mixture was heated at 55 C for 3.5 hours. The reaction mixture was cooled to 0 C and the precipitate was collected, washed with water, then dried by lyophilization to give 6-iodo-quinazoline-2,4-diol as a lavender solid, (849 mg, 78%). HNMR (500 MHz, DMSO) δ6.72 (d, 1H), 7.53 (d, 1H), 7.95 (s, 1H), LCMS m/e 286.98 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]1[CH2:12][C@@H:11]([CH3:13])[N:10]([CH2:14][CH:15](O)[CH:16]=[CH:17][C:18]2[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=2)[C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2].[C:28]([OH:32])(=[O:31])[CH2:29]C.[CH2:33](C(CC)(CC)C([O-])([O-])[O-])[CH3:34]>C(OCC)(=O)C>[CH2:33]([O:32][C:28](=[O:31])[CH2:29][C@@H:17]([C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=1)[CH:16]=[CH:15][CH2:14][N:10]1[C@H:11]([CH3:13])[CH2:12][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])[C:9]1=[O:26])[CH3:34]
Reactant: Cc1ncc(C=CC(O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]2C)cn1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CCC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](C=CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)c1cnc(C)nc1
Temperature: 25 °C

Procedure:
A stirred solution of 5-2 (300 mg) and propionic acid (5 mg) in triethylorthoacetate (6 mL) was heated at 140° C. for 3 hours, then cooled to ambient temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, dried over magnesium sulfate, and filtered. Following evaporative removal of the solvent, the residue was purified by flash column chromatography (silica gel, 9:1 ethyl acetate/methanol) to give 5-3 as a tan foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.I[C:11]1[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=1>>[CH3:18][C:13]1[CH:12]=[C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[N:2]2)[CH:16]=[C:15]([CH3:17])[CH:14]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: c1ccc2[nH]ncc2c1
Product: Cc1cc(C)cc(-n2ncc3ccccc32)c1
Yield: 96 %

Procedure:
Using general procedure A, indazole (148 mg, 1.25 mmol) was coupled with 5-iodo-m-xylene (150 μL, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 10:1; 10 mL fractions). Fractions 4-10 provided 222 mg (96% yield) of the product as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.20 (d, J=1.0 Hz, 1H), 7.83−7.74 (m, 2H), 7.46−7.40 (m, 1H), 7.36 (s, 2H), 7.25−7.19 (m, 1H), 7.01 (s, 1H), 2.43 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])(O)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:6][CH:7]=1.S(Br)([Br:26])=O.Cl>C(#N)C.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Br:26])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:6][CH:7]=1
Reactant: OC(Cn1cncn1)(c1ccc(Cl)cn1)c1ccc(Cl)cc1Cl
Reactant: O=S(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: Clc1ccc(C(Br)(Cn2cncn2)c2ccc(Cl)cc2Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(5-Chloropyrid-2-yl)-1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol (0.55 g, 1.49 mmoles) was stirred in acetonitrile (20 ml) and thionyl bromide (0.4 g, 1.92 mmoles) was added. After 1 hr. at room temperature, a small amount of starting material remained (as shown by t.l.c.) and thus a further 0.1 g of thionyl bromide was added and the solution was stirred overnight at room temperature. The acetonitrile was then removed by evaporation under reduced pressure and the residue was basified with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3×40 ml). The combined organic extracts were dried over magnesium sulfate and evaporated and the residue was flash chromatographed on silica (230-400 mesh), eluting with ethyl acetate:hexane (1:3, v:v) to give an oil which was dissolved in dry ether and treated with ethereal hydrogen chloride. The white solid which precipitated (0.23 g) was recrystallized from isopropanol/diisopropyl ether to give the title compound as white crystals, 0.112 g (16%), m.p. 130° -150° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].[CH3:9]O.Cl>>[NH2:1][C@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH3:9])=[O:4]
Reactant: C=CC[C@@H](N)C(=O)O
Reactant: CO
Agent: Cl
Product: C=CC[C@@H](N)C(=O)OC
Yield: 98 %

Procedure:
A solution of (R)-2-aminopent-4-enoic acid (18d) (5 g, 43.5 mmol) in MeOH.HCl (2.4M, 50 mL) was stirred at 70° C. overnight. The mixture was concentrated under reduced pressure to give compound 18e (5.5 g, 98% yield), which was used without purification.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][C:11]2[C:12]([C:16]([F:19])([F:18])[F:17])=[N:13][O:14][CH:15]=2)[N:9]=1.[Cl-:20].[NH4+:21]>>[ClH:20].[F:17][C:16]([F:19])([F:18])[C:12]1[C:11]([CH2:10][CH:8]2[NH:9][C:3](=[NH:21])[CH2:4][CH2:5][CH2:6][CH2:7]2)=[CH:15][O:14][N:13]=1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COC1=NC(Cc2conc2C(F)(F)F)CCCC1
Product: Cl
Product: N=C1CCCCC(Cc2conc2C(F)(F)F)N1

Procedure:
The title product of Example 123 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=O)[CH3:14])[CH:10]=[CH:11][CH:12]=1.[ClH:16].NO.O.C[N:21]([CH:23]=O)C>>[Cl:16][C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1)=[CH:14][C:23]#[N:21]
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: Cl
Reactant: CN(C)C=O
Agent: NO
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: N#CC=C(Cl)c1cccc(Cl)c1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
A solution of POCl3 was slowly added to anhydrous DMF over a period of 20 minutes and the temperature was maintained around 30° C. 3′-Chloroacetophenone solution in anhydrous DMF was added to the above solution and the reaction temperature was allowed to rise to around 50° C. Hydroxylamine HCl was added to the reaction solution, portionwise, over 1 hour. A volume of 500 mL of water was added to form precipitate, stirred for 1 hour and the precipitate was collected on a Buchner funnel, washed with H2O, and dried to afford a yellow crystalline compound, mp 60-62° C. 1H NMR (DMSO-d6) δ1.60 (s, 6H), 7.30 (d, 1H, J=8.41 Hz), 7.41 (d, 1H, J=8.41 Hz), 10.47 (s, 1H); MS(+APCI)m/z 213(M+H); Anal. Calc. For C9H9ClN2O2: C, 50.84; H, 4.27; N, 13.17. Found: C, 50.99; H, 4.28; N, 12.98.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][N:7]=[CH:8][C:9]1[S:17][C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:23][S:24]C1C2C=C(C=O)SC=2N=CN=1.N1C2SC(C=O)=CC=2C=NC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][N:7]=[CH:8][C:9]1[S:17][C:12]2[N:13]=[CH:14][N:15]=[C:16]([S:24][CH3:23])[C:11]=2[CH:10]=1
Reactant: CSc1ncnc2sc(C=O)cc12
Reactant: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Agent: O=Cc1cc2cncnc2s1
Product: COc1ccc(CN=Cc2cc3c(SC)ncnc3s2)cc1OC

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 14 but using 4-(methylthio)thieno[2,3-d]pyrimidine-6-carbaldehyde (intermediate 15) in place of thieno[2,3-d]pyrimidine-6-carbaldehyde (intermediate 13). White solid (76 mg, 97%);
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[NH2:16][CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]3)[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNc2ccnc(Nc3cccc(Cl)c3)n2)C1
Temperature: 25 °C
Yield: 42.4 %

Procedure:
To a solution of 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (500 mg, 2.08 mmol) and tert-butyl (3S)-3-(aminomethyl)pyrrolidine-1-carboxylate (625 mg, 3.12 mmol) in THF (10 mL) is added diisopropylethylamine (0.73 mL, 4.16 mmol). The reaction is heated at reflux for 18 hours and then cooled to room temperature. The crude reaction is partitioned between EtOAc and sat. NaHCO3. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (MeOH/CH2Cl2) to afford 356 mg (42% yield) of the desired compound: MS (ESI, pos. ion) m/z: 404 (M+1).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[Si:15]([CH2:22][CH2:23][CH:24]([OH:30])[C:25]([CH3:29])([CH3:28])[C:26]#[N:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C1C=CN=CC=1.CCOCC>[Si:15]([CH2:22][CH2:23][CH:24]([O:30][C:8](=[O:10])[CH3:9])[C:25]([CH3:29])([CH3:28])[C:26]#[N:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C#N)C(O)CC[Si](C)(C)C(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OC(CC[Si](C)(C)C(C)(C)C)C(C)(C)C#N
Temperature: 0 °C

Procedure:
14.43 g (142.64 mmol) of triethylamine and 200 mg of 4-dimethylaminopyridine (DMAP), dissolved in 128 ml of MTB-ether, and, at 0° C., 14.56 g (142.64 mmol) of acetic acid anhydride are added to 28.24 g (109.7 mmol) of 5-tert-butyldimethylsilyl-2,2-dimethyl-3(R,S)-hydroxy-pentane-nitrile, the title compound of Example 6a, and it is stirred for 5 hours at room temperature. It is poured onto 2 l of ice water and extracted twice with 300 ml each of MTB-ether. The combined MTB-phases are washed once with 300 ml of 5% hydrochloric acid and then with water. It is evaporated to the dry state in a vacuum. The residue is purified by flash chromatography on silica gel (hexane/MTB-ether).