Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[N:27][C:28]5[N:29]([N:31]=[CH:32][C:33]=5[CH2:34][CH3:35])[CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[I-].[Li+]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[N:27][C:28]5[N:29]([N:31]=[CH:32][C:33]=5[CH2:34][CH3:35])[CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(CC)cnn5c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCc1cnn2cc(-c3cc(-c4nc5cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c6ccc(Cl)cc6)c5s4)ccn3)cnc12
Temperature: 170 °C

Procedure:
A mixture of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(3-ethylpyrazolo[1,5-a]pyrimidin-6-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (31 mg, 0.048 mmol) and lithium iodide (200 mg) in pyridine (0.5 mL) was heated in microwave at 170° C. for 1 h. Reaction mixture was diluted with ethyl acetate, washed with 5% acetic acid solution, brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 10% MeOH/CH2Cl2). Lyophilization gave desired product. LCMS-ESI+: calc'd for C33H31ClN5O3S: 612.2 (M+H+); Found: 612.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 9.33 (d, J=2.1 Hz, 1H), 9.02 (d, J=2.1 Hz, 1H), 8.60 (d, J=5.1 Hz, 1H), 8.56-8.49 (m, 2H), 8.29 (s, 1H), 8.02 (s, 1H), 7.85 (tt, J=7.7, 1.8 Hz, 1H), 7.77-7.61 (m, 4H), 7.61-7.49 (m, 3H), 7.43 (ddd, J=7.7, 4.4, 1.5 Hz, 2H), 5.24 (s, 1H), 2.78 (q, J=7.6 Hz, 2H), 2.56 (s, 3H), 1.30 (t, J=7.6 Hz, 3H), 0.96 (d, J=6.8 Hz, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]S(C)(=O)=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Na+].[I-:23]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][I:23])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)Nc1ccc(C=CCCCCCS(C)(=O)=O)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(C=CCCCCCI)cc1
Yield: 117.7 %

Procedure:
To a solution of 2.641 g (8.11 mmol) of N-acetyl-4-(7-methanesulfonyl-1-heptenyl)-aniline in 60 mL of acetone was added 1.832 g (12.2 mmol) of NaI. The reaction mixture was refluxed for 19 hr. Then, filtration and evaporation of solvent gave 3.410 g (quant) of iodide 34, which was used as is in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:22]([O:24]CC2C=CC=CC=2)=[O:23])=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>CO>[CH2:1]([O:8][C:9]1[C:10]([C:22]([OH:24])=[O:23])=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ncnc(C(=O)OCc3ccccc3)c2OCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2ncnc(C(=O)O)c2OCc2ccccc2)cc1
Temperature: 90 °C

Procedure:
To a solution of benzyl 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylate P71 (90 mg, 0.22 mmol) in methanol (5 mL) was added lithium hydroxide monohydrate (46 mg, 1.10 mmol). The reaction mixture was heated in a microwave reactor at 90° C. for 10 minutes. The organic solvent was evaporated under reduced pressure. Ethyl acetate and 1 N hydrochloric acid were added. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The solid product was dried under reduced pressure to afford the desired 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylic acid P72 (70 mg, 0.22 mmol).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C[O:6][C:7](=O)[CH:8]([Cl:10])[CH3:9]>>[Cl:10][CH:8]([CH3:9])[C:7]([NH:4][CH2:3][CH2:1][OH:2])=[O:6]
Reactant: COC(=O)C(C)Cl
Reactant: NCCO
Product: CC(Cl)C(=O)NCCO
Reaction time: 60 h
Yield: 91.5 %

Procedure:
Ethanolamine (13.45 g, 0.22 mol) is added to 21.5 ml (0.2 mol) of 2-chloropropionic acid methylester. The mixture solidifies after standing at room temperature for 60 h. The solid is triturated with ethylacetate, the crystals are filtered off and dried to afford 27.75 g of the title compound as white crystals, mp. 64° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.C1C(=O)N([Cl:18])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([Cl:18])[C:3]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: Clc1nc[nH]c2nccc1-2
Solvent: ClCCl
Product: Clc1cnc2[nH]cnc(Cl)c1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-chloro-1H-pyrrolo[2,3-d]pyrimidine (1 g, 6.5 mmol, commercially available from e.g. Sigma-Aldrich, Apollo or Alfa Aesar) was dissolved in DCM (30 ml) and then NCS (1.04 g, 7.8 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, and then heated at 60° C. for 22 hours. After cooling a light yellow solid was obtained by filtration of the desired product in 1.2 g. LCMS [MH+] 188.0@1.42 min (5 min run)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:26][CH2:25]3)=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 25 °C

Procedure:
1,1-Dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (0.34 g, 95%) was prepared as a white solid from 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (Example 146, Step 4, 0.20 g, 0.80 mmol), 1,1-dimethylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate (0.33 g, 1.12 mmol), K2CO3 (0.23 g, 1.60 mmol) in DMF (7 mL) in a manner similar to Example 139, Step 3. The reaction mixture was cooled to ambient temperature, and poured into water (50 mL). The precipitate was collected and washed with water, air dried to give 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.40 (bs, 1H), 8.14 (d, 2H, J=7.5 Hz), 8.01 (d, 2H, J=7.3 Hz), 7.80-7.70 (m, 1H), 7.34 (bs, 1H), 4.18 (bs, 2H), 3.91 (d, 2H, J=6.1 Hz), 3.07 (s, 3H), 2.85-2.65 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.45 (s, 9H), 1.40-1.20 (m, 2H); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: C([O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)(=O)C.C(C1C(=O)C(Cl)=C(Cl)C(=[O:22])C=1C#N)#N.C1(=O)C2C(=CC=CC=2)CCC1>O1CCOCC1.O>[OH:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:22]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: COc1ccc2c(c1OC(C)=O)CCCC2
Agent: O=C1CCCc2ccccc21
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1O)CCCC2=O

Procedure:
The 5-hydroxy isomer 7 was converted to 5-acetoxy-6-methoxy-1,2,3,4-tetrahydronaphthalene (9) in 95% yield. Reaction of the 9 with DDQ in dioxane-water led to the formation of tetralone 10 as a single isomer in 96% yield. The correct position of the keto group was confirmed by single-crystal X-ray crystallography. The acetate was removed by treating tetralone 10 with sodium bicarbonate in methanol to form 5-hydroxy-6-methoxy-1-tetralone (11).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[NH:7][C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.[H-].[Na+].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.O>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[N:7]([CH2:23][CH2:22][CH2:21][CH2:20][Br:19])[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3
Reactant: Nc1ccc2c3c(cccc13)C(=O)NC2=O
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc2c3c(cccc13)C(=O)N(CCCCBr)C2=O
Temperature: 25 °C

Procedure:
A suspension of 10.6 g of 6-amino-1H-benz[de]-isoquinoline-1,3(2H)-dione in 250 ml of dimetnylformamide was stirred as 2.6 g of 50% sodium hydride in mineral oil was added. The initial orange suspension turned deep red in color. After ten minutes, a solution of 27 g of 1,4-dibromobutane in 50 ml of dimethylformamide was added. A slightly exothermic reaction was noted, and a deep red solution resulted. The mixture was then stirred at room temperature for sixteen hours, and drowned into 600 ml of cold water. A tarry brown precipitate was obtained, and on standing, bright yellow crystals developed in the supernatant. These were collected and recrystallized from aqueous alcohol to yield the pure title compound mp 175°-176° C. The brown precipitate required several recrystallizations from aqueous alcohol to afford more of the pure title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[C:9]([CH3:17])[N:8]=1.[CH:19]1([C:22]2[C:23]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:24][CH:25]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[C:23]([N:31]3[CH2:32][CH2:33][N:34]([C:11]([C:10]4[C:9]([CH3:17])=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:16][CH:15]=4)=[O:13])[CH2:35][CH2:36]3)=[N:24][CH:25]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:27]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)nc1C
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: Cc1nc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 66.4 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylnicotinate (300 mg) described in Preparation Example 37 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (297 mg) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Example 109, the title compound (355 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[Br:19][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccc(Cl)cc1OCc1ccccc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(CBr)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of {4-chloro-2-[(phenylmethyl)oxy]phenyl}methanol (for a preparation see intermediate 6) (0.501 g, 2.02 mmol) in DCM (10 ml) at −10 to −15° C., under nitrogen, was added a solution of phosphorus tribromide (0.190 ml, 2.02 mmol, Aldrich) in DCM (5 ml) dropwise. The solution was allowed to warm to ambient temperature and stirred for 4.5 h. To the reaction mixture in an ice-water bath was added dropwise saturated aqueous sodium hydrogen carbonate (5 ml). The mixture was diluted with water (45 ml) and dichloromethane (55 ml). The phases were separated and the aqueous phase washed with DCM (30 ml). The combined organic extracts were washed with water (10 ml). The organic extract was dried (MgSO4), filtered and the solvent removed in vacuo to give 1-(bromomethyl)-4-chloro-2-[(phenylmethyl)oxy]benzene (0.505 g) as a colourless gum.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.[CH3:16]O>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CO
Reactant: Cc1[nH]c2ccccc2c1CC(=O)O
Agent: Cl
Product: COC(=O)Cc1c(C)[nH]c2ccccc12
Yield: 90.7 %

Procedure:
2-(2-Methyl-1H-indol-3-yl)acetic acid (11.7 g, 61.84 mmol) was weighed and added into 100 mL methanol. Concentrated hydrochloric acid 0.7 mL was added dropwise. It was reacted at 70° C. for 4 hours, cooled, rotate evaporated to dryness, extracted with ethyl acetate, washed twice with NaHCO3 aqueous solution. The organic phase was dried and rotate evaporated to dryness to obtain a red brown solid 11.4 g, at a yield of 90.7%.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:13][CH2:14][C:15]([OH:17])=[O:16]>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:13][C@H:14]([C:15]([OH:17])=[O:16])[CH2:10][OH:11]
Reactant: NCC(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: N[C@@H](CO)C(=O)O

Procedure:
The formation of t-Boc--Phe--SerOH is obtained by the same process, but using 1.1 mmol of lyophilised hydrated serine in place of cysteine and 1 mmol of phenylalanine protected by t-Box and activated in place of glycine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@H:9]2[CH2:22][NH:23][C:24](=[O:29])[CH2:25][O:26][CH2:27][CH3:28])=[CH:4][C:3]=1[F:30].C(OCC)(=O)C.Cl>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH2:22][NH:23][C:24](=[O:29])[CH2:25][O:26][CH2:27][CH3:28])=[CH:4][C:3]=1[F:30]
Reactant: CCOCC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOCC(=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 171.8 %

Procedure:
To tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-{[(ethoxyacetyl)amino]methyl}-1,4-oxazepane-4-carboxylate (125 mg) was added 4.0 M hydrogen chloride-ethyl acetate solution (2.11 ml), and the mixture was stirred at room temperature for 1 hr. The residue obtained by concentration under reduced pressure was recrystallized from ethanol-diisopropyl ether to give the title compound (92.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[C:4]([C@H:26](O)[CH3:27])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:26]2[CH3:27]
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2-c2ccc(F)cc2[C@@H](C)O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
N-{4′-fluoro-2′-[(1R)-1-hydroxyethyl]-1,1′-biphenyl-2-yl}-4-methoxybenzene-sulfonamide (0.12 g, 0.29 mmol) and triphenylphosphine (0.31 g, 1.2 mmol) were dissolved in tetrahydrofuran (10 mL) and diethylazodicarboxylate (0.21 g, 0.19 mL, 1.2 mmol) was added. The solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the mixture was dissolved in ethyl acetate and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (3:1 hexane: ethyl acetate) to yield the title compound as a crystalline solid (0.085 g, 79% ), m.p. 181-182° C.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15](OC)=[O:16])=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Li+].[BH4-].CCCCCC.C(OCC)(=O)C>C1COCC1>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccn(S(=O)(=O)c2ccc(C)cc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc(CO)c2)cc1
Yield: 90.3 %

Procedure:
To a solution of 10 (15.6 g, 0.063 mol) in 250 mL anhydrous THF was added LiBH4 (1.8 g, 0.08 mol) at 60° C. water bath for 24 h. The reaction was quenched by the addition of 1 M H2SO4 solution. The resulting solution was extracted with dichloromethane. The extracts were washed with saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulphate, filtered and evaporated under vacuum to give light yellow solid which subjected to flash chromatography (silica gel, hexane:ethyl acetate=2:1) to afford 11 as a white solid (14.3 g, 90%). 1H NMR (CDCl3, δ/ppm), 7.74 (m, 2H), 7.29 (d, 2H), 7.12-7.09 (m, 2H), 6.29 (m, 1H), 4.46 (s, 2H), 2.39 (s, 3H), 1.86 (b, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH:7]([C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)[CH3:8])[CH2:5]Cl.C([O-])(=O)C.[Na+]>[Pd].C(O)(=O)C>[NH:12]1[CH:13]=[C:9]([CH:7]([CH3:8])[CH:4]([NH2:3])[CH3:5])[N:10]=[CH:11]1
Reactant: CC(c1c[nH]cn1)C(N)CCl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: CC(N)C(C)c1c[nH]cn1
Yield: 63.9 %

Procedure:
A mixture of 2 g (8.1 mmol) 2-amino-1-chloro-3-(1H-imidazol-4-yl)butane dihydrochloride, 1.3 g (16.2 mmol) sodium acetate and 100 ml 10% acetic acid, are hydrogenated over 0.5 g 10% palladium on activated carbon for 10 days at 10 bar and ambient temperature. The catalyst is removed by filtration and the filtrate brought to pH 1 by addition of concentrated hydrochloric acid. After evaporation the oily residue is dissolved in dry ethanol and inorganic material is removed by filtration. By addition of petrolether the title compound crystallizes as dihydrochloride. Recrystallization from methanol/acetonitrile yields 0.72 g (40.4%) [3-(1H-imidazol-4yl)but-2-yl]amine.2HCl.0.25 methanol as colorless crystals, melting point: 249°-254° C. (decomp.).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([C:43](O)=[O:44])=[N:35]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:43]([C:36]3[C:37]4[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=4)[NH:34][N:35]=3)=[O:44])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)c3n[nH]c4ccccc34)cc2)cc1

Procedure:
The titled compound was prepared following the procedure H using methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate and 1H-indazole-3-carboxylic acid as a yellow oil (55%). 1H NMR (MeOD, 300 MHz) δ 8.05 (m, 1H), 7.17-7.56 (m, 13H), 6.88 (m, 2H), 5.06 (s, 1H), 5.02 (s, 1H), 4.68 (m, 4H), 3.76 (s, 3H), 2.62 (t, J=7.4 Hz, 2H), 1.60 (m, 2H), 1.34 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). M− (ESI): 584.4; M+ (ESI): 5.86.3. HPLC, Rt: 5.49 min (Purity: 84.1%).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH:7]([CH:14]1[O:19][CH2:18][C:17](=O)[N:16](C)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].[CH3:26]O.Cl>C1COCC1>[N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH:7]([CH:14]1[O:19][CH2:18][CH2:17][NH:16][CH:15]1[CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: CN1CC(C(Oc2ccccc2[N+](=O)[O-])c2ccccc2)OCC1=O
Agent: Cl
Solvent: C1CCOC1
Product: CC1NCCOC1C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Reaction time: 1 h

Procedure:
Into a solution of 12.3 g of 2-[α-(2-nitro-phenoxy)-benzyl]-4-methyl-morpholin-5-one in 350 ml of anhydrous THF there was slowly added dropwise 77 ml of a molar solution of BH3 in THF. After the addition, the mixture was refluxed for 6 hours. The excess of BH3 was eliminated with MeOH at room temperature, and dropwise addition was then made to the reaction mixture of 50 ml of 23% HCl and stirring carried out for 1 hour at 60° C. The whole was concentrated to a small volume and the residue diluted with water, thereafter alkalinizing with NaOH and extracting with CH2Cl2. After normal processing and crystallization from isopropyl ether, the 2-[α-(2-nitro-phenoxy)-benzyl]-3-methyl-morpholine, m.p. 78°-81° C. (8.1 g; 68%) was obtained.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][NH:4][C:5]1[C:6]2[O:31][CH:30]=[CH:29][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[N:17][N:18]3COCC[Si](C)(C)C)=[CH:14][CH:13]=2)[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:18]1[C:19]2[C:15](=[CH:14][CH:13]=[C:12]([NH:11][C:9]3[N:10]=[C:5]([NH:4][CH2:3][C:2]([F:32])([F:33])[F:1])[C:6]4[O:31][CH:30]=[CH:29][C:7]=4[N:8]=3)[CH:20]=2)[CH:16]=[N:17]1
Reactant: C[Si](C)(C)CCOCn1ncc2ccc(Nc3nc(NCC(F)(F)F)c4occc4n3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)CNc1nc(Nc2ccc3cn[nH]c3c2)nc2ccoc12
Temperature: 30 °C
Reaction time: 6 h
Yield: 19.1 %

Procedure:
N4-(2,2,2-trifluoroethyl)-N2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)furo[3,2-d]pyrimidine-2,4-diamine (1.08 g, 2.257 mmol) was dissolved in DCM (15 mL). TFA (10 mL, 130 mmol) was added. The resulting mixture was stirred at about 30° C. for about 6 h. The mixture was concentrated in vacuo. The residue was diluted with DCM (30 mL) and the pH was adjusted to about pH=9.0 with concentrated NH4OH. The solvents were removed under reduced pressure and the resulting mixture was purified by preparative-HPLC (Table 2, method w) to afford N2-(1H-indazol-6-yl)-N4-(2,2,2-trifluoroethyl)furo[3,2-d]pyrimidine-2,4-diamine (0.15 g, 19%): LC/MS (Table 2, Method h) Rt=1.79 min; MS m/z: 349 (M+H)+. Syk IC50=A
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:40][O:41][CH3:42])[C:4]([CH3:39])=[C:5]([C:28]([O:30]COC(=O)C(C)(C)C)=[O:29])[CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9]>C(OC(C)C)(C)C.O>[CH3:39][C:4]1[N:3]([CH2:40][O:41][CH3:42])[C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:16])[CH3:17])=[O:9])[C@@H:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:5]=1[C:28]([OH:30])=[O:29]
Reactant: COCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: O
Solvent: CC(C)OC(C)C
Product: COCN1C(C)=C(C(=O)O)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 1.2 g of bis(pivaloyloxymethyl) 1,4-dihydro-2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate obtained in Example 1 or 2 as a substrate. To the substrate solution was added 300 mg of Lipase B, and the reaction system was stirred at room temperature for 3 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 0.9 g (yield: 95%) of (S)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl)-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a colorless crystal.