Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=[O:4].[OH:13][C@@H:14]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>C1COCC1.CCOCC.C1CCCCC1>[CH:3]([O:13][C@H:14]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15]1)=[O:4]
Reactant: O=C(N[C@H]1CC[C@@H](O)C1)OCc1ccccc1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CO[C@H]1CC[C@H](NC(=O)OCc2ccccc2)C1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
Diethyl azodicarboxylate (1.78 g) was added dropwise to a stirred solution of N-(cis-3-hydroxycyclopentyl)carbamic acid, (phenylmethyl) ester (1.19 g), triphenylphosphine (2.68 g) and formic acid (0.47 g) in THF (65 ml) under nitrogen at room temperature. The resulting solution was stirred for 2 h, and concentrated to give a residue which was stirred in ether (20 ml) at ca -10° under nitrogen for 1 h. The mixture was diluted with cyclohexane (20 ml), and the solid was filtered off and washed with ether:cyclohexane (1:1; 3×ca. 20 ml). The combined filtrate and washings were concentrated, and the resultant residue was purified by FCC eluting with ethyl acetate:cyclohexane (2:3) to give the title compound (1.18 g), m.p. 45°-48°.
Reaction SMILES: C[O:2][C:3]1[CH:31]=[CH:30][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]4[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][C:19]=4[C:26]([F:29])([F:28])[F:27])=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.CCCCCC.CCOC(C)=O>C(Cl)Cl.B(Br)(Br)Br>[OH:24][C:21]1[CH:22]=[CH:23][C:18](/[CH:17]=[CH:16]/[C:13]2[CH:12]=[CH:11][C:10]([C:8]3[S:9][C:5]4[CH:4]=[C:3]([OH:2])[CH:31]=[CH:30][C:6]=4[N:7]=3)=[CH:15][CH:14]=2)=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:20]=1
Reactant: COc1ccc(/C=C/c2ccc(-c3nc4ccc(OC)cc4s3)cc2)c(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1ccc(/C=C/c2ccc(-c3nc4ccc(O)cc4s3)cc2)c(C(F)(F)F)c1
Yield: 81.5 %

Procedure:
Prepared as described in the Demethylation section above using 6-methoxy-2-(4-{(E)-2-[4-methoxy-2-(trifluoromethyl)phenyl]ethenyl}phenyl)-1,3-benzothiazole (0.30 g, 0.68 mmol) in dry DCM (10 ml) and BBr3 in DCM (1.0 M, 1.40 ml, 1.40 mmol) at −78° C. give the title compound (0.229 g, 81%) as a yellow solid after work-up and flash chromatography (1:1 Hexane/EtOAc).
Reaction SMILES: C1([C@@H]2C(C3C=CC=CC=3)(C3C=CC=CC=3)OB(C)N2)CCCCC1.[Br:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].CO>O1CCCC1.C(OCC)(=O)C>[Br:25][CH2:26][C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28]
Reactant: O=C(CBr)c1ccccc1
Agent: CB1N[C@H](C2CCCCC2)C(c2ccccc2)(c2ccccc2)O1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@@H](CBr)c1ccccc1
Temperature: 25 °C

Procedure:
A 0.25 M tetrahydrofuran solution of (R)-4-cyclohexyl-5,5-diphenyl-2-methyl-1,3,2-oxazaborolidine (0.4 mL) (prepared as in example 12) was added to a dry flask containing borane dimethylsulfide complex (0.05 mL, 0.5 mmol) under nitrogen. The mixture was stirred at room temperature for I hour and then, a solution of bromoacetophenone (99.5 mg, 0.5 mmol) in dry tetrahydrofuran (3 mL) was added to the borane/(R)-4-cyclohexyl-5,5-diphenyl-2-methyl-1,3,2-oxazaborolidine complex over 20 minutes via a syringe pump. The reaction was stirred at room temperature for 2 hours. Methanol was added to quench the reaction and then the solvents were removed by evaporation. The residue obtained was dissolved in ethyl acetate, washed with 1M hydrochloric acid and filtered through a silica gel plug. The filtrate was concentrated to provide (R)-2-bromo-1-phenylethanol. The enantiomeric excess=96.2% and was measured by HPLC (Chiralcel OD-H column, mobile phase, hexane/isopropyl alcohol 9:1, flow rate=0.6 mL/min).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]([O:20][CH3:21])[CH2:9]1)=O)(C)(C)C.[ClH:22]>CO>[ClH:22].[CH3:21][O:20][CH:10]1[CH:11]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][NH:8][CH2:9]1
Reactant: COC1CN(C(=O)OC(C)(C)C)CC1Nc1ccccc1
Agent: Cl
Solvent: CO
Product: COC1CNCC1Nc1ccccc1
Reaction time: 8 h

Procedure:
In 100 ml of methanol was dissolved 1.98 g (0.0068 mole) of 1-t-butoxycarbonyl-3-methoxy-4-phenylaminopyrrolidine obtained as described above, and 23.5 ml of 6N hydrochloric acid was added thereto. The mixture was left to stand at room temperature overnight. The solvent was removed under reduced pressure, and the residue was washed with ethanol to obtain 1.71 g of 3-methoxy-4-phenylaminopyrrolidine hydrochloride as white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C#N)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N4CCCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-cyano-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J28) (302 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (420 mg, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[CH2:25][CH:24]([C:28]([O:30]C)=[O:29])[CH2:23]2)=[CH:18][CH:17]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26](=[O:27])[CH2:25][CH:24]([C:28]([OH:30])=[O:29])[CH2:23]2)=[CH:20][CH:21]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(N4CC(C(=O)O)CC4=O)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-5-oxopyrrolidine-3-carboxylate (Step 2, 0.5 g, 1.18 mmol) in MeOH/THF (2 mL: 2 mL) solution was added 1.77 mL of 1 N NaOH. The reaction was stirred at RT for 8 h. The solution was concentrated in vacuo to dryness and was acidified with 1 N HCl. The white precipitate was collected by filtration and was washed with 50% EtOAc/hexanes to give the title compound as a white solid. MS (ESI pos. ion) m/z: 409.3 (M+H). Calc'd Exact Mass for C22H20N2O6: 408.4.
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[N+:27]([C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N+:27]([C:30]1[CH:31]=[C:32]([NH:36][C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CCC(=O)Nc2cccc([N+](=O)[O-])c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.5 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (402 mg, 2.10 mmol) and Et3N (2934, 2.10 mmol) in anhydrous DCM (17 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (480 mg, 2.00 mmol) and DMAP (24 mg, 0.20 mmol) and stir the resulting solution for 5 min. 3-Nitro-phenylamine (88) (414 mg, 3.00 mmol) and stir the reaction solution 24 h at rt. Quench reaction solution with sat. aqu. NH4Cl and water, separate layers and extract aqu. layer with EtOAc (3 times). Wash combined organic layer with brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+1) to obtain N-(3-Nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-propionamide (89) (508 mg, 70%) as a yellow solid. 1H NMR (400 MHz, CDCl3): 2.65 (t, 2H, J=7.5 Hz); 2.98 (t, 2H, J=7.5 Hz); 3.79 (s, 6H); 3.81 (s, 3H); 6.42 (s, 2H); 7.41 (s, 1H); 7.45 (t, 1H, J=8.3 Hz); 7.84 (d, 1H, J=8.3 Hz); 7.92 (d, 1H, J=8.3 Hz); 8.31 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([NH:19]C(=O)CCCC)=[N:5]2.N1CCCC1.O1CCCC1>O>[NH2:19][C:6]1[C:7]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][C:9]2[C:4]([N:5]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2
Reactant: CCCCC(=O)Nc1nc2ccc(Cl)cc2nc1NC(=O)CCCC
Solvent: C1CCNC1
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(=O)Nc1nc2ccc(Cl)cc2nc1N
Reaction time: 168 h

Procedure:
A solution of 12 parts of 6-chloro-2,3 bis(valeramido)quinoxaline and 2.5 parts of pyrrolidine in 220 parts of tetrahydrofuran was permitted to stand at ambient temperature for seven days. The solution was then poured into 750 parts of water and the solid which separated was removed by filtration and washed with water, pressed dry, and washed with hexane. The crude product was dissolved in 108 parts of boiling ethyl acetate and the resulting solution filtered. Upon addition of 100 parts of hexane and subsequent cooling, the solution deposited 3 parts of 3-amino-6-chloro-2-valeramidoquinoxaline as a pale yellow solid, m.p. 224°-228° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13].BrC1C=C(C=CC=1)C=O.C(N(CC)CC)C>C1COCC1>[OH:14][CH2:10][CH2:11][C:12]#[C:13][C:9]1[CH:2]=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: O=Cc1ccccc1Br
Reactant: C#CCCO
Agent: O=Cc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cccc(C#CCCO)c1

Procedure:
This is an example of a coupling reaction to form compounds such as the title compound by coupling compounds such as bromo benzaldehyde and 3-butyn-1-ol. A 1-L, 3-necked round-bottom flask was equipped with a magnetic stirring bar, a condenser with a nitrogen inlet, and two stoppers. The vessel was charged with 3-bromobenzaldehyde (18.5 g, 0.1 mol), 3-butyn-1-ol (10.5 g, 0.15 mol), triethylamine (100 mL), and THF (100 mL). To this mixture was then added PdCl2 (PPh3)2 (1.4 g, 2 mmol) and CuBrMe2S (0.405 g, 4 mmol). In other examples, the title compound was also obtained by using CuI together with a palladium-containing entity. The reaction mixture was heated to reflux using a heating mantle. After 4 h when TLC (thin layer chromatography) showed complete consumption of the bromide, the mixture was allowed to cool to room temperature, transferred to a 1-L round-bottom flask and concentrated under reduced pressure. The residue was dissolved in 250 mL of ethyl acetate. The solution was washed with water and brine, dried over MgSO4, and filtered. After filtration, the solvents were removed from the filtrate by evaporation under reduced pressure to obtain the title compound as pale yellow oil (16.8 g, yield 97%). Purity of the compound so obtained was determined by HPLC to be greater than 95%. TLC (Rf=0.32, SiO2, ethyl acetate/hexanes, 1:1). MS (electro spray, positive mode), M+ 174. 1H NMR (400 MHz, CDCl3)δ: 2.72 (t, 2H, J=6.3), 3.84 (t, 2H, J=6.2), 7.47 (t, 1H, J=7.7), 7.66 (dt, 1H, J=7.7, 1.4), 7.81 (dt, 1H, J=7.7, 1.4), 7.91 (t, 1H, J=1.4), 9.98 (s, 1H). It was found in the context of this invention, as illustrated by the embodiment given in this example, that the amount of palladium catalyst can be reduced down to catalyst amounts in the order of 0.1% (mol/mol). In contrast, conventional methodologies rely on Pd catalyst amounts in the range 1%-5%, with the percentages referred to the same units. This reduction in the amount of palladium catalyst leads to a significant cost reduction. Furthermore, this reduction in the amount of palladium catalyst leads to a reduction in the palladium contamination of the final product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH:28]([C@@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)([CH3:30])[CH3:29]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:32]3[C@H:31]([CH:28]([CH3:30])[CH3:29])[CH2:35][O:34][C:33]3=[O:36])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC(C)[C@@H]1COC(=O)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C(C)C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 48.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 9 and (R)-4-isopropyloxazolidin-2-one (258 mg), the title compound (487 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)=[O:9]
Reactant: Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: Nc1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1

Procedure:
A solution of 5-methyl-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 9; 400 mg, 1.65 mmol), 3-pyridinamine (311 mg, 3.30 mmol), HOBT (379 mg, 2.48 mmol) and EDC (475 mg, 2.48 mmol) in DMF (5 ml) was stirred at room temperature overnight. The reaction mixture was poured into water (20 ml), filtered and the solid was washed by water and dried to yield the title compound as a white solid. 220 mg.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:10](=[O:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C1COCC1.[BH4-].[Na+]>[Cl-].[Na+].O.CCOC(C)=O.CCCCCC>[CH2:24]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C@@H:10]([OH:12])[CH3:11])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.83 h
Yield: 91 %

Procedure:
To (S)-3-(dibenzylamino)-4-(4-(trifluoromethyl)phenyl)butan-2-one (8.00 g, 19.4 mmol) in a 1 L round bottom flask was added MeOH (106 mL) and THF (35 mL). The mixture was cooled to −20° C. in a dry ice/acetone bath, and sodium borohydride (1.54 g, 40.8 mmol) was added. After 50 minutes, brine (200 mL) was added, and the mixture was extracted with ether (2×200 mL). The ether was washed with brine (50 mL), dried over sodium sulfate, and evaporated to provide an aqueous/oily mixture. The mixture was taken up in EtOAc (100 mL), washed with brine (50 mL), and the brine was back extracted with EtOAc (2×50 mL). The combined organic layers were dried over sodium sulfate and evaporated to a colorless oil. The oil was taken up in hexane and a white precipitate quickly formed. The precipitate was dissolved in hot hexane and left to stand at room temperature. Needles slowly formed, and the flask was cooled at −20° C. for 16 hours. The solid was recovered by filtration through a medium scintered glass funnel. The filtrate was evaporated and 1.4 g of colorless oil was recovered. The oil was dissolved in 6 mL hexane and cooled at −20° C. After 6 hours, the hexane was decanted and the white solid was placed under high vacuum. The two crops were combined to provide (2S,3S)-3-(dibenzylamino)-4-(4-(trifluoromethyl)phenyl)butan-2-ol (7.30 g, 90.8% yield) as a white crystalline solid. LCMS (ES+) m/z=414.3; 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (d, J=6.06 Hz, 3H) 2.67-2.75 (m, 1H) 2.76-2.88 (m, 1H) 3.15 (dd, J=14.28, 5.67 Hz, 1H) 3.38 (d, J=13.30 Hz, 2H) 3.70-3.81 (m, 1H) 3.94 (d, J=13.30 Hz, 2H) 4.13 (s, 1H) 7.16-7.35 (m, 12H) 7.57 (d, J=7.83 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].I[CH2:23][CH2:24][CH3:25]>>[F:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH3:19])[N:8]([CH2:23][CH2:24][CH3:25])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc2c(F)cccc2c1-c1ccc(OC)cc1C
Yield: 45.8 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.150 g, 0.52 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and 1-iodopropane (0.075 mL, 0.7 mmol) to give the title compound (0.071 g) as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>C(#N)C.CCOC(C)=O.[Cu]I>[CH3:16][N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: C#C[Si](C)(C)C
Reactant: CN1CCN(C(=O)c2cccc(I)c2)CC1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)c2cccc(C#C[Si](C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
(3-Iodophenyl)(4-methylpiperazin-1-yl)methanone (1.15 g, 3.5 mmol) and ethynyl-trimethyl-silane (0.58 mL, 4.2 mmol) in dry acetonitrile (30 mL) were purged with nitrogen and treated with TEA (0.97 mL, 7.0 mmol, 2 eq.), CuI (0.033 g, 0.17 mmol) and Pd (Ph3P)2Cl2 (0.120 g, 0.17 mmol). The reaction was stirred at room temperature for 2 h, then was diluted with EtOAc (30 mL), washed with water (2×20 mL), brine, dried over sodium sulphate, and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 95/5) to afford the title compound (0.95 g, 91%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:15]([S:40][C:10]=2[CH2:9]1)=[N:16][C:17]([CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39])=[C:18]([Cl:32])[C:19]=3[C:20]1[CH:25]=[CH:24][C:23]([O:26]C(C)C)=[C:22]([O:30][CH3:31])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:15]([S:40][C:10]=2[CH2:9]1)=[N:16][C:17]([CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39])=[C:18]([Cl:32])[C:19]=3[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:30][CH3:31])[CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2c(Cl)c(CN3CCCC3=O)nc3sc4c(c23)CCN(Cc2ccccc2)C4)ccc1OC(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(-c2c(Cl)c(CN3CCCC3=O)nc3sc4c(c23)CCN(Cc2ccccc2)C4)ccc1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 25.3 %

Procedure:
A solution of titanium tetrachloride (6.3 g) in dichloromethane (10 ml) was added dropwise to a solution of the compound (3.8 g) obtained in Example 23B in dichloromethane (75 ml) under ice-cooling, and the mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was poured over ice-aqueous saturated solution of sodium bicarbonate and the insoluble was filtered off, the organic layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (7:3, v/v) to yield 7-benzyl-3-chloro-4-(4-hydroxy-3-methoxyphenyl)-2-(2-oxo-1-pyrrolidinylmethyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine (0.89 g, 25%), which was then recrystallized as colorless prismatic crystals having a melting point of 190 to 191° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=O)[O:20]CC)=[C:14]([CH3:24])[CH:13]=3)[C:6]=2[N:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].O>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][CH:19]=[O:20])=[C:14]([CH3:24])[CH:13]=3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)Nc1ccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cn2nnc3c(-c4ccco4)nc(N)nc32)ccc1NC=O
Temperature: 25 °C
Yield: 7.1 %

Procedure:
A mixture of ethyl 4-((5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl)methyl)-2-methylphenylcarbamate (318 mg, 0.81 mmol) and LiAlH4 (62 mg, 1.62 mmol) in dry THF (30 mL) was refluxed overnight, cooled to room temperature, treated with 13% aqueous NaOH solution (0.1 mL) then water (0.3 mL), stirred for 30 min, filtered through Celite and concentrated in vacuo. The resulting solid was triturated with THF and filtered to give the title compound (20 mg, 7%) as a yellow solid.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([C:32]([OH:34])=O)[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)CCl.Cl.[CH3:40][O:41][C:42](=[O:50])[C@H:43]([CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])[NH2:44]>ClCCl>[CH3:40][O:41][C:42](=[O:50])[C@H:43]([CH2:45][C:46]([CH3:48])([CH3:47])[CH3:49])[NH:44][C:32](=[O:34])[C@@H:26]([CH2:27][C:28]([CH3:29])([CH3:30])[CH3:31])[NH:25][C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:24]
Reactant: COC(=O)[C@@H](N)CC(C)(C)C
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)(C)C)NC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
HOBt (3 equivalents, 39.4 g, 292 mmol), N-methylmorpholine (3 equivalents, 32.1 ml, 291.8 mmol), N-tert-butoxycarbonyl-3-tert-butyl-D-alanine (Example 6A, 1.0 equivalent, 97.3 mmol), EDC (2 equivalents, 37.3 g, 194.6 mmol) and again N-methylmorpholine (2 equivalents, 21.4 ml, 194.5 mmol) are added successively at −20° C. to a solution of 3-tert-butyl-L-alanine methyl ester hydrochloride (1.1 equivalents, 21 g, 107 mmol) in dichloromethane p.a. (1.4 l). The reaction mixture warms slowly (about 12 h) to RT, whereby complete conversion of the amine component is observed by means of HPLC. The reaction mixture is then washed with a saturated aqueous sodium hydrogen carbonate solution (300 ml), 5% aqueous citric acid (2×500 ml), a saturated aqueous sodium hydrogen carbonate solution (500 ml) and a saturated sodium chloride solution. The reaction mixture is dried over sodium sulfate and filtered. The mixture is concentrated to dryness in vacuo and then dried further under high vacuum. 36 g (96% of theory) of the title compound are obtained, which is reacted without further purification.