Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([OH:7])=[O:6].[CH:13]1[CH:18]=CC=C[CH:14]=1.O>C(O)(C)C>[ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([O:7][CH:13]([CH3:18])[CH3:14])=[O:6]
Reactant: c1ccccc1
Reactant: CC(C)C[C@H](N)C(O)C(=O)O
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CC(C)C[C@H](N)C(O)C(=O)OC(C)C

Procedure:
Hydrogen chloride was passed into a solution of 4.0 g of (2RS, 3S)-3-amino-2-hydroxy-5methylhexanoic acid in 50 ml of isopropyl alcohol with stirring under ice-cooling. To the reaction solution was added 100ml of benzene, and the mixture was heated under reflux for 10 minutes with removal of water as formed during the reaction using a molecular seives. The reaction mixture was evaporated under reduced pressure to obtain 5.7 g of isopropyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[C:8]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([CH3:14])=[CH:10][C:11]=2[CH3:13])[NH:6][CH2:5]1.I[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].CCOC(C)=O>CN(C=O)C>[CH2:23]([N:6]1[C:7]2[C:12](=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=2[NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:20])[CH3:19])[CH:4]([CH2:3][CH2:2][OH:1])[CH2:5]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCI
Reactant: Cc1cc(C)c2c(c1NC(=O)C(C)(C)C)NCC2CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCN1CC(CCO)c2c(C)cc(C)c(NC(=O)C(C)(C)C)c21
Temperature: 70 °C
Reaction time: 10 h
Yield: 13.5 %

Procedure:
N-[3-(2—Hydroxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethyl-propanamide (1.6 g) was dissolved in DMF (15 ml) and 1-iodooctane (3.9 g) and K2 CO3 (2.3 g) were added, which was followed by stirring at 70° C for 10 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=5/1−1/2) to give 300 mg of the title compound.
Reaction SMILES: [B:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7](O)=[O:8])([OH:3])[OH:2].[CH3:15][NH:16][CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:15][N:16]([CH3:17])[C:7]([C:6]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:4]([B:1]([OH:3])[OH:2])[CH:5]=1)=[O:8]
Reactant: CNC
Reactant: COc1ccc(C(=O)O)cc1B(O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N(C)C)cc1B(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
To a solution of 700 mg (3.57 mmol) 3-borono-4-methoxybenzoic acid in 23 ml DMF, 3.6 ml (7.14 mmol) dimethylamine, 1.5 g (3.93 mmol) HATU and 1.57 ml (14.29 mmol) NMM were added and stirred at RT for 2 hours. The reaction mixture was extracted with EtOAc and water. The organic phase was dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC (Prep. HPLC method 1, gradient: 15-30% in 16 minutes). The fractions containing product were combined and extracted twice with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated to afford 361 mg (1.619 mmol, 45.3% yield) of the title compound as a colorless solid. LCMS: (M+H)=224; tR=0.54 min (LC-MS 4). 1H-NMR (d6-DMSO, 400 MHz) δ ppm 7.56 (m, 1H) 7.44 (dd, 1H) 6.99 (d, 1H) 3.81 (s, 3H) 2.93 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH3:2].[C:14]([Cl:19])(=O)[C:15](Cl)=O>CN(C)C=O.O1CCCC1>[Cl:19][C:14]1[CH:15]=[CH:7][C:6]([C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[O:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 196.8 %

Procedure:
N,N-dimethylformamide(1 drop) was added to a tetrahydrofuran solution(40 ml) of pimelic acid monoethyl ester(25.5 g), and thereto oxalyl chloride(18.8 g) was added dropwise. After stirring for 2 hours at room temperature, the reaction mixture was concentrated. The residue was added dropwise to a mixture of chlorobenzene(61.0 g) and aluminum chloride anhydrous (36.1 g) under ice water. After stirring for 3 hours, the reaction mixture was poured into 1N-hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 6-(4-chlorobenzoyl)hexanate (37.7 g, 97%) as an oily substance.
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:12][S:13]S(C)(=O)=O>O.C(O)C>[CH3:12][S:13][S:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CS)cc1
Reactant: CSS(C)(=O)=O
Solvent: CCO
Solvent: O
Product: CSSCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
4-(mercaptomethyl)benzoic acid (36, 500 mg, 2.97 mmol) was dissolved in water (10 mL) and cooled in an ice bath. The cooled solution stirred as methyl methanethiolsulfonate (413 mg, 3.27 mmol) dissolved in ethanol (5.00 mL) was added. Following addition, the cooling bath was removed and the reaction was stirred overnight at room temperature. After proceeding overnight, the reaction was diluted with saturated sodium chloride and extracted with ether. The combined extracts were washed with sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was isolated using silica flash chromatography eluting with a gradient of 40-60% ethyl acetate in hexanes containing 1% acetic acid over 20 min. to give 482 mg of the desired product, 4-((methyldisulfanyl)methyl)benzoic acid (37b), in 73.5% yield. 1H NMR (CDCl3) δ 2.121 (3H, s), 3.938 (2H, s), 7.457 (2H, d, J=8.4 Hz), 8.068 (2H, d, J=8 Hz).
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[C:19]([O:23][C:24]([N:26]1[C@H:30]([C:31]([OH:33])=O)[CH2:29][S:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[NH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C@H:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:40]([OH:42])=[O:41]>CN(C=O)C.O>[C:47]([O:46][C:44]([NH:43][C@@H:39]([CH2:38][CH2:37][CH2:36][CH2:35][NH:34][C:31]([C@@H:30]1[CH2:29][S:28][CH2:27][N:26]1[C:24]([O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:25])=[O:33])[C:40]([OH:42])=[O:41])=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (247 mg, 0.892 mmol) was added to a solution of (R)-3-(tert-butoxycarbonyl)thiazolidine-4-carboxylic acid (Compound tk81) (208 mg, 0.892 mmol) in DMF (1 ml), and the mixture was stirred at room temperature for 30 minutes. A solution of (S)-6-amino-2-((tert-butoxycarbonyl)amino)hexanoic acid (220 mg, 0.892 mmol) in water (1 ml) was added dropwise at room temperature over 3 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes. The reaction solution was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol) to afford (S)-2-((tert-butoxycarbonyl)amino)-6-((R)-3-(tert-butoxycarbonyl)thiazolidine-4-carboxamido)hexanoic acid (Compound tk82) (156 mg, 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](O)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[K+].[Br-]>C(Cl)(Cl)Cl.CO>[C:13]1([C:12]2[O:11][C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[N:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(O)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=[N+]([O-])c1ccc2oc(-c3ccccc3)nc2c1
Yield: 85 %

Procedure:
Prepared from 2-amino-4-nitrophenol and benzoic acid, in a manner similar to that of Example 9b. Yield: 85%; Rf (9/1 chloroform/methanol): 0.92; Elem. anal. C13H8N2O3; theory C, 65.00; H, 3.35; N, 11.66. found C, 64.54; H, 3.35; N, 11.85. IR (KBr): 1615, 1530, 1345 cm−1.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22](=O)[CH3:23]>C(#N)C>[CH3:23][C:22]1[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[S:1][C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC(=O)c1cnccc1Cl
Reactant: CCOC(=O)CS
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc2ccncc2c1C
Temperature: 25 °C
Yield: 17.2 %

Procedure:
To a solution of ethyl 2-mercaptoacetate (5.52 g, 0.046 mol) and triethylamine (5.52 g, 0.055 mol) in acetonitrile (100 mL) at room temperature was added 1-(4-chloropyridin-3-yl)ethanone (6.5 g, 0.042 mol). The reaction mixture was heated at reflux for 18 hours. Upon cooling to room temperature, the solvent was evaporated and the residue obtained partitioned between ethyl acetate and water. The organic layer was dried over anhydrous NaHSO4, filtered and concentrated. The oily residue was passed through a pad of silica (ethyl acetate/hexane: 5/1) to afford ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate (1.6 g, 22%). LCMS (FA) ES+ 222; 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 7.98 (d, J=17.6 Hz, 1H), 4.37 (d, J=7.2 Hz, 2H), 3.58 (t, J=5.9 Hz, 2H), 1.38 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.Cl[CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].CC(C)([O-])C.[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOP(=O)(CCl)OCC
Reactant: COc1ncccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)n1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.5 %

Procedure:
A solution of 2-methoxy-3-nitropyridine (6.92 g, 44.9 mmol) and diethyl chloromethylphosphonate (7.00 mL, 44.9 mmol) in 40 mL DMSO was added drop wise to a stirred mixture of potassium tert-butoxide (15.1 g, 134.6 mmol) and 40 mL DMSO. The mixture was stirred at room temperature for 30 minutes, after which, it was poured into a 1N HCl/ice mixture and extracted with methylene chloride. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (DCM:EtOAc1:1). The slower eluting regioisomer was collected and confirmed to be the desired product (750 mg, 5.5% yield). MS (ES+): m/z 305.16 (100) [MH+]; HPLC: tR=1.16 min (UPLC, Analytical).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:5][Mg]Br.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:27][C:28](=[O:30])[CH3:29])=[N:17][C:18]=1[CH:19]=[N:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22].[Cl-].[NH4+]>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:27][C:28](=[O:30])[CH3:29])=[N:17][C:18]=1[C@@H:19]([NH:20][S:21]([C:23]([CH3:25])([CH3:26])[CH3:24])=[O:22])[CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: CC(=O)Nc1ccc(Br)c(C=N[S@@](=O)C(C)(C)C)n1
Reactant: Fc1cc(F)cc(C[Mg]Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Br)c([C@H](Cc2cc(F)cc(F)c2)NS(=O)C(C)(C)C)n1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
(3,5-Difluorobenzyl)magnesium bromide (0.25 M in ether, 10 ml, 2.5 mmol) was added dropwise to a solution of (S)—N-(5-bromo-6-(((tert-butylsulfinyl)imino)methyl)pyridin-2-yl)acetamide (1D, 0.47 g, 1.36 mmol) in DCM (5 ml) at 78° C. The reaction was stirred for 3 h at −78° C. Ammonium chloride (aq, 10 mL) was added to the reaction and the mixture was allowed to warm to r.t. The mixture was extracted with EtOAc (2×30 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product contained a mixture of diastereomers which were used in the next step without further purification. MS (m/z) 474.1 [M+H]+.
Reaction SMILES: [O-]CC.[Na+].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]([O:25]C(=O)C2C=CC=CC=2)[CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][C:10]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:8])([CH3:7])[CH3:6]>>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]([OH:25])[CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[CH:11][C:10]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=2[O:44][C:45]2[C:50]1=[CH:49][CH:48]=[CH:47][CH:46]=2)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1ccc(CC[C@@H](CC2CCCCC2)OC(=O)c2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: CC[O-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(CC[C@H](O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
13.3 ml of a 0.58M ethanolic solution of sodium ethoxide were added to 1.62 g (2.57 mmol) of (S)-N-[2-t-butyl-5-(4-cyclohexyl-3-benzoyloxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 101), and the resulting mixture was stirred at room temperature for 8 hours, after which it was heated under reflux for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with water and then extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 150 g of silica gel, using a 2:8 by volume mixture of acetonitrile and benzene as the eluent. The concentrated eluate was recrystallized from diisopropyl ether, to give 1.14 g (yield 85%) of the title compound, melting at 141°-142° C.
Reaction SMILES: C([N:8]1[C@@H:13]2[C@@H:14]([C:16]3[NH:17][C:18](=[O:21])[NH:19][N:20]=3)[CH2:15][C@@:9]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([O:22][CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd].C(O)C>[F:37][C:34]([F:35])([F:36])[C:26]1[CH:25]=[C:24]([CH2:23][O:22][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:15][C@@H:14]3[C:16]2[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=1
Reactant: O=c1[nH]nc([C@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)[nH]1
Agent: [Pd]
Solvent: CCO
Product: O=c1[nH]nc([C@H]2C[C@]3(c4ccccc4)N[C@H]2CC[C@H]3OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(2,4-dihydro-3H-1,2,4-triazol-3-on-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 86; 66 mg, 0.11 mmol), 10% palladium on charcoal (180 mg), ethanol (10 ml) was stirred under hydrogen atmosphere (1 atm) at +60° C. for 1.5 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30][CH2:31][CH3:32])=[CH2:29])CCC>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>[CH2:31]([O:30][C:28]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1)=[CH2:29])[CH3:32]
Reactant: CC(c1ccc2c(cnn2C)c1)c1cnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=C(OCC)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Yield: 95.6 %

Procedure:
The title compound (415.0 mg, 86%, 90% pure) was synthesized from 6-chloro-3-[1-(1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (390.0 mg, 1.25 mmol), tributyl(1-ethoxyvinyl)stannane (497.0 mg, 1.38 mmol) and Pd(PPh3)4 (145 mg, 0.13 mmol) using the same procedure as described in the synthesis of compound 69.3. LCMS (method A): [MH]+=348, tR=5.86 min.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.Cl.[O:13]([C:20]1[CH:25]=[CH:24][C:23]([NH:26]N)=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH3:1][N:2]([CH3:10])[CH:3]1[CH2:4][C:5]2[C:24]3[C:23](=[CH:22][CH:21]=[C:20]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:25]=3)[NH:26][C:6]=2[CH2:7][CH2:8]1
Reactant: CN(C)C1CCC(=O)CC1
Reactant: NNc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CN(C)C1CCc2[nH]c3ccc(Oc4ccccc4)cc3c2C1

Procedure:
To a solution of 14.1 g. of 4-dimethylaminocyclohexanone in 100 ml. of a 6-N solution of hydrogen chloride in absolute ethyl alcohol was added 23.5 g. of 4-phenoxyphenylhydrazine hydrochloride and the mixture was heated at reflux for 6 hours. The mixture was filtered, the filtrate was made alkaline with 10% potassium hydroxide and extracted with chloroform, and the chloroform extract was washed with water and evaporated to dryness under reduced pressure to give 3-(dimethylamino)-6-phenoxy-1,2,3,4-tetrahydrocarbazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[S:31][CH:32]=[C:33]([C:35]([OH:37])=O)[N:34]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:49]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:50].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:48][CH:47]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[S:31][CH:32]=[C:33]([C:35]([N:54]6[CH2:55][CH2:56][N:51]([CH2:49][CH3:50])[CH2:52][CH2:53]6)=[O:37])[N:34]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:44][CH:43]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3nc(C(=O)O)cs3)cn2)cc1
Reactant: CCN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CCN(C(=O)c2csc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)n2)CC1

Procedure:
To 2-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-thiazole-4-carboxylic acid (77 mg), N-ethylpiperazine (36 μl), WSCI (68 mg), HOBt (48 mg) and triethylamine (48 μl) were left to act in DMF (3 ml), to obtain a crude product of [2-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-thiazol-4-yl]-(4-ethyl-piperazin-1-yl)-methanone, and then the PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-120) as an ivory powder (38 mg, 63%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(C=O)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(CN2CCOCC2)c1
Reaction time: 8 h

Procedure:
3-[5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-3-methyl-isoxazol-4-yl]-benzaldehyde (25 mg, 0.05 mmol) and morpholine (0.3 ml) were mixed with DCE (0.5 ml) in an microwave tube. Sodium triacetoxyborohydride (15 mg, 1.4 equiv) was added, the tube sealed, and nitrogen atmosphere introduced. After 1 hr more sodium triacetoxyborohydride (15 mg) was added and the reaction left stirring overnight. TLC analysis showed that the reaction had not gone to completion so a drop of acetic acid was added and the reaction again left stirring overnight after which the reaction was quenched with 1M NaHCO3 solution (7 ml) and extracted into EtOAc (5 ml). This was dried over MgSO4 and the solvent removed in vaccuo to provide 13 mg of the crude product as an off white powder which was taken over to the deprotection step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: c1c[nH]cn1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1ccnc1

Procedure:
Using general procedure 2 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.166 g, 0.63 mmol) and imidazole (0.052 g, 0.76 mmol) gives the title compound.
Reaction SMILES: Cl.[Cl:2][CH:3]=[CH:4][CH2:5][O:6][NH2:7].C([O-])(=O)C.[Na+].[OH:13][C:14]1[CH2:19][CH:18]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([C:28](=[O:32])/[CH:29]=[CH:30]/[CH3:31])[C:21]=2[CH3:33])[CH2:17][C:16](=[O:34])[C:15]=1[C:35](=O)[CH2:36][CH3:37]>C(O)C>[Cl:2][CH:3]=[CH:4][CH2:5][O:6][N:7]=[C:35]([C:15]1[C:14](=[O:13])[CH2:19][CH:18]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([C:28](=[O:32])/[CH:29]=[CH:30]/[CH3:31])[C:21]=2[CH3:33])[CH2:17][C:16]=1[OH:34])[CH2:36][CH3:37]
Reactant: C/C=C/C(=O)c1c(C)cc(C)c(C2CC(=O)C(C(=O)CC)=C(O)C2)c1C
Reactant: NOCC=CCl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C/C=C/C(=O)c1c(C)cc(C)c(C2CC(=O)C(C(CC)=NOCC=CCl)=C(O)C2)c1C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
3-Chloroallyloxyamine hydrochloride (0.3 g) and then anhydrous sodium acetate (0.2 g) were added to a solution of 3-hydroxy-5-(3-crotonyl-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one (0.7 g) in anhydrous ethanol (80 ml). The mixture was stirred briefly then allowed to stand at room temperature for 16 hours. The ethanol was removed by evaporation under reduced pressure using a rotary evaporator. The residue was treated with chloroform and the organic phase was washed twice with water (50 ml). The chloroform layer was dried over magnesium sulphate and the solvent was removed by evaporation under reduced pressure to give the product 2-[1-(3-chloroallyloxyimino)propyl]-3-hydroxy-5-(3-crotonyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.7 g, 85%) as a colourless oil. Proton magnetic spectrum (CDCl3 ; δ in ppm); 1.19 (3H, t); 1.92 (3H, d, J=7 Hz); 2.09 (3H, s); 2.19 (3H, s); 2.39 (3H, s); 2.2-4.0 (7H, m); 4.4-4.8 (2H, m); 5.86.7 (4H, m); 6.86 (1H, s); 15.2 (1 H, bs).