Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@:5]1([C:25]#[CH:26])[CH:11]=[CH:10][C@H:9]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH2:7][CH3:8])[C@@H:20]1[C:15](=[CH:16][C:17](=[O:24])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:3])[CH3:2].O1CCCC1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].S(=O)(=O)(O)O>CC(C)=O.CCCCCC>[C:1]([O:4][C@@:5]1([C:25]#[CH:26])[CH:11]=[CH:10][C@H:9]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH2:7][CH3:8])[C@@H:20]1[C:15](=[CH:16][C@@H:17]([OH:24])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:3])[CH3:2]
Reactant: C#C[C@]1(OC(C)=O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C#C[C@]1(OC(C)=O)C=C[C@H]2[C@@H]3CCC4=C[C@@H](O)CC[C@@H]4[C@H]3CC[C@@]21CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Analogously to Example 13, 1.5 g. of 17β-acetoxy-17α-ethynyl-18-methyl-4,15-estradien-3-one in 40 ml. of tetrahydrofuran is reacted with 4.5 g. of lithium tri-(tert.butoxy)-aluminum hydride in 30 ml. of tetrahydrofuran. After 1 hour, the solution is introduced into ice water which contains sulfuric acid and worked up analogously to Example 13. After chromatography of the crude product on silica gel with 5-8% acetone-hexane, 530 mg. of 17β-acetoxy-17α-ethynyl-18-methyl-4,15-estradien-3β-ol is obtained.
Reaction SMILES: O=C(Cl)[O:3][C:4]([Cl:7])(Cl)[Cl:5].Cl.Cl.[Cl:11][CH2:12][CH2:13][N:14]([CH2:22][CH2:23][Cl:24])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.CCN(CC)CC>CCl.C1COCC1>[ClH:5].[Cl:11][CH2:12][CH2:13][N:14]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:4]([Cl:7])=[O:3])=[CH:19][CH:20]=1)[CH2:22][CH2:23][Cl:24]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Agent: CCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)Nc1ccc(N(CCCl)CCCl)cc1
Reaction time: 0.5 h

Procedure:
A solution of diphosgene (197 mg, 1.2 mmol.) in dry CH3Cl was added dropwise to a suspension of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride (37) (0.306 g, 1.0 mmol) in dry THF (25 mL) containing Et3N (0.5 mL) in an ice bath with vigorous stirring for 30 min. It formed crude p-[(N,N-bis(2-chloroethyl)amino)]phenylcarbamoyl chloride hydrochloride (38). The reaction mixture was filtered through a pad of Celite and washed with THF (5 mL). The filtrate and washings were combined and was then added dropwise into a solution of 3-amino-5-(4-methylacridin-9-ylamino)phenyl]-methanol18 (0.329 mg, 1.0 mmol) in dry DMF (20 mL) containing Et3N (0.5 mL) at 0° C. and stirred at room temperature for 16 h. The solvent was removed by distillation under reduced pressure to dryness and the residue was dissolved in CHCl3/MeOH and mixed with silica gel (5 g) and then evaporated in vacuo to dryness. The residue was put on the top of a silica gel column (2×20 cm) and chromatographed using CHCl3/MeOH (100:2 v/v) as eluent. The fractions containing the main product were combined and concentrated in vacuo and the residue was recrystallized from CHCl3/MeOH to give 1-{4-[bis(2-chloroethyl)amino]phenyl}-3-[3-hydroxymethyl-5-(4-methylacridin-9-ylamino)phenyl]urea (16, BO-1050), 179 mg (30%); mp 251-252° C.; 1H NMR (DMSO-d6) δ 3.64-3.71 (8H, m, 4×CH2), 4.00 (3H, s, Me), 4.47 (2H, d, J=5.1 Hz, CH2) 5.11 (1H, t, J=5.1 Hz, exchangeable, OH), 6.35 (1H, s, ArH), 6.68 (2H, d, J=8.8 Hz, 2×ArH) 6.75 (1H, s, ArH), 6.88-7.18 (4H, m, 4×Ar H), 7.24 (2H, d, J=8.8 Hz, 2×ArH) 7.52 (2H, s, 2×ArH), 7.83 (2H, s, 2×Ar H), 8.25 (1H, s, ArH) 8.40 (1H, s, ArH), 10.24 (1H, s, exchangeable, NH). Anal. Calcld. for (C32H31Cl2N5O2.3H2O): C, 59.81; H, 5.80; N, 10.89. Found: C, 59.74; H, 5.79; N, 9.67.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:24]([NH:23][S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)CCCCC=NS(=O)C(C)(C)C
Reactant: COc1cncc(OC)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)CCCCC(NS(=O)C(C)(C)C)c1c(OC)cncc1OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of commercially available 4-bromo-3,5-dimethoxypyridine (4.998 g; 22.92 mmol) in anh. THF (90 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (14.30 ml; 22.88 mmol). The resulting solution was further stirred at −78° C. for 10 min. A solution of methyl 6-((tert-butylsulfinyl)imino)hexanoate (3.780 g; 15.28 mmol) in anh. THF (10 ml) was then added to the cooled reaction mixture, and stirring at −78° C. was continued for 60 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (80 ml), Et2O (250 ml) and water (75 ml). The separated organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded methyl 6-(3,5-dimethoxypyridin-4-yl)-6-(1,1-dimethylethylsulfinamido)hexanoate as a yellow oil. LC-MS (conditions A): tR=0.49 min.; [M+H]+: 387.11 g/mol.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([C@@H:10]1[CH2:14][S:13][C@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:11]1[C:22](=[O:39])[CH2:23][NH:24][C:25](=[O:38])[NH:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34]([O:36]C)=[O:35])[CH:30]=[CH:31][CH:32]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO.O.[OH-].[Na+]>[C:3]([O:7][C:8]([C@@H:10]1[CH2:14][S:13][C@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:11]1[C:22](=[O:39])[CH2:23][NH:24][C:25](=[O:38])[NH:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34]([OH:36])=[O:35])[CH:30]=[CH:31][CH:32]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.1 %

Procedure:
At a temperature in the vicinity of 25° C., 0.12 g of potassium hydroxide is added to a solution of 0.95 g of methyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenylacetate in 6 cm3 of a water/methanol (30/70 by volume) mixture. The reaction mixture is stirred for 3 hours at a temperature in the vicinity of 25° C. then concentrated to about half under reduced pressure. The solution obtained is diluted with 40 cm3 of water, washed with 2 times 30 cm3 of ethyl ether, then brought to a pH of 2 by addition of 2.1 cm3 of a 1N aqueous sulphuric acid solution. The insoluble product is separated by filtration and purified by chromatography on silica [eluent: ethyl acetate/methanol (90/10 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. The amorphous product thus obtained (0.26 g) is dissolved in a 1N aqueous sodium hydroxide solution. This solution is filtered, then acidified by addition of a 1N aqueous sulphuric acid solution. The product thus precipitated is separated by filtration, washed with 3 times 10 cm3 of water, then dried in air. 0.26 g of (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenylacetic acid, melting at 110° C., is thus obtained ([α]D20 =+51.1°±1.6° (C=0.528%; DMF), [proton NMR (200 MHz, DMSO D6 plus several drops of CD3COOD, δ in ppm, J in Hz), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 1.55 (s, 9H, --C(CH3)3); 3.34 and 3.52 (2dd, J=12.5 and 6.5, 2H, S--CH2 --); 3.51 (s, 2H, ArCH2COO--); 3.8 and 4.07 (2d, J=17.5, 2H, N--COCH2 --N); 5.02 (t, J=6.5, N--CH--COO); 6.55 (s, 1H, S--CH--N); 6.85 (bd, J=8, 1H, in position 4 on CO--NH--Ph); 7.05 to 7.4 (m, 6H, aromatic); 7.93 (bt, J=8.5, 1H, in position 6 on S--CH--Ph--)], [infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2980, 2930, 2700 to 2250 (broad band), 1735, 1610, 1615, 1595, 1560, 1490, 1460, 1370, 1230, 1155, 760, 705].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:15]1([CH2:21][CH2:22][CH2:23]O)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:23][CH2:22][CH2:21][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: OCCCN1CCOCC1
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-6-hydroxy-7-methoxy-quinazoline and 3-Morpholin-4-yl-propan-1-ol. LC/ESI-MS: m/z=338 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[C:4]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:3]=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH2:40][NH2:41])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39]>O>[CH3:28][C:22]1([CH3:29])[CH2:21][CH:20]([NH:19][C:4]2[N:5]=[C:6]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:7]=[C:2]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]([CH2:40][NH:41][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:17])([CH3:18])[CH2:10]4)[N:5]=[C:4]([NH:19][CH:20]4[CH2:25][C:24]([CH3:26])([CH3:27])[NH:23][C:22]([CH3:28])([CH3:29])[CH2:21]4)[N:3]=3)[CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:2]3[N:3]=[C:4]([NH:19][CH:20]4[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]4)[N:5]=[C:6]([NH:8][CH:9]4[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12][C:13]([CH3:16])([CH3:15])[CH2:14]4)[N:7]=3)[N:3]=2)[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23]1
Reactant: CC1(C)CC(Nc2nc(Cl)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Reactant: NCCCCC(CN)CCCN
Solvent: O
Product: CC1(C)CC(Nc2nc(NCCCCC(CCCNc3nc(NC4CC(C)(C)NC(C)(C)C4)nc(NC4CC(C)(C)NC(C)(C)C4)n3)CNc3nc(NC4CC(C)(C)NC(C)(C)C4)nc(NC4CC(C)(C)NC(C)(C)C4)n3)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1

Procedure:
5.1 g of 2-chloro-4,6-bis[N-(2,2,6,6-tetramethyl-4-piperidyl)amino]-1,3,5-triazine [prepared as described in Preparation 9(b)] were reacted with 0.7 g of 1,8-diamino-4-aminomethyloctane, following the procedure described in Example 9. After completion of the reaction, the reaction mixture was poured into water and extracted with chloroform. The extract was dried over anhydrous potassium carbonate, and the solvent was distilled off. The residue was purified by column chromatography through silica gel, eluted with a 8:2:1 by volume mixture of ethyl acetate, ethanol and triethylamine, to give the desired Compound No. 1 in the form of crystals melting at 148°-158° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:31]1([NH:34][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:14][CH2:15]3)=[N:20][CH:21]=2)[CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (87 mg, 0.213 mmol) and cyclopropanamine (18.24 mg, 0.319 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.065 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (10-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-cyclopropyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide (70.3 mg, 0.157 mmol, 73.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.49-0.56 (m, 2 H) 0.62-0.70 (m, 2H) 1.82-2.02 (m, 3 H) 2.11-2.22 (m, 1 H) 2.40 (t, J=4.93 Hz, 4 H) 2.78 (tq, J=7.34, 3.86 Hz, 1H) 3.34 (br. s., 2 H) 3.36-3.44 (m, 1 H) 3.49-3.64 (m, 5 H) 3.94-4.03 (m, 1 H) 6.81 (d, J=8.59 Hz, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.61 (d, J=1.77 Hz, 1 H) 7.90 (dd, J=9.09, 2.53 Hz, 1H) 8.20 (d, J=4.04 Hz, 1 H) 8.54 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C24H29N7O2, 448; found, 448.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:55])([CH3:54])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:53])([C@@:17]4([CH3:52])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([NH:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH2:40]2)[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].[ClH:56]>C1COCC1>[ClH:56].[CH3:52][C@:17]12[C@@:16]3([CH3:53])[C@@H:25]([C@:26]4([CH3:29])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:54])([CH3:55])[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[CH:28][CH2:27]4)[CH2:24][CH2:23][C@@H:22]1[C@H:21]1[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]1([NH:36][CH2:37][CH2:38][N:39]1[CH2:40][CH2:41][NH:42][CH2:43][CH2:44]1)[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
A mixture of tert-butyl 4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)amino)ethyl)piperazine-1-carboxylate (150 mg, 0.198 mmol) and HCl (0.248 mL, 0.992 mmol) in THF (4 mL) was stirred at 20° C. for 18 hours. The reaction mixture was concentrated under reduced pressure to provide the desired product as brown solid (120 mg, 87%). LCMS: m/e 656.7 (M+H)+, 1.62 min (method 11).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[CH2:29][OH:30])[CH2:6][O:7][C:8]1[CH:9]=[C:10](/[C:14](/[CH2:23][CH2:24][CH3:25])=[CH:15]\[CH2:16][CH2:17]C(OCC)=O)[CH:11]=[CH:12][CH:13]=1.C[Mg]Br>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[CH2:29][OH:30])[CH2:6][O:7][C:8]1[CH:9]=[C:10](/[C:14](/[CH2:23][CH2:24][CH3:25])=[CH:15]\[CH2:16][CH2:17][C:8]([CH3:9])([OH:7])[CH3:13])[CH:11]=[CH:12][CH:13]=1
Reactant: CCC/C(=C/CCC(=O)OCC)c1cccc(OCc2ccc(CO)c(CO)c2)c1
Agent: C[Mg]Br
Product: CCC/C(=C/CCC(C)(C)O)c1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 84(c), by reacting 1 g (1.6 mmol) of ethyl (Z)-5-[3-(3,4-bis-hydroxymethylbenzyloxy)phenyl]oct-4-enoate (prepared in a manner similar to Examples 84(a-b)) with 5.4 ml (16 mmol) of a 3.0M solution of methylmagnesium bromide, a colourless oil is obtained (m=516 mg; Y=81%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:26])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[S:19][C:20]([CH2:23][CH3:24])=[CH:21][CH:22]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:25].CCN(C(C)C)C(C)C.[C:36](O)(=[O:39])[CH2:37][OH:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[CH2:23]([C:20]1[S:19][C:18]([C:16]2[O:15][N:14]=[C:13]([C:9]3[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][CH:3]([OH:26])[CH2:2][NH:1][C:37](=[O:38])[CH2:36][OH:39])=[C:7]([CH3:25])[CH:8]=3)[N:17]=2)=[CH:22][CH:21]=1)[CH3:24]
Reactant: O=C(O)CO
Reactant: CCc1ccc(-c2nc(-c3cc(C)c(OCC(O)CN)c(C)c3)no2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1ccc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
To a cold solution (0° C.) of 1-amino-3-{4-[5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (32 mg, 86 μmol) in DCM (1 mL), DIPEA (45 mg, 345 μmol), glycolic acid (13 mg, 172 μmol) and finally TBTU (33 mg, 101 μmol) is added. The mixture is stirred at rt for 1 h before it is diluted with EA and washed with water. The aq. phase is extracted back with EA. The combined org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by crystallisation from acetonitrile to give N-(3-{4-[5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (7 mg) as a white solid; LC-MS: tR=0.95 min, [M+1]+=432.16.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:10]1[C:9]([O:8][CH2:7][C:5]2[S:6][C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)=[C:3]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:4]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2-c2cccnc2)cc1
Temperature: 120 °C
Yield: 551.3 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.1 g, 0.02 mmol) in DMF:H2O (2:1), 3-pyridine boronic acid (0.054 g, 0.04 mmol), potassium phosphate (0.056 g, 0.025 mmol) was added. The reaction mixture was degassed for 10 min and then dichlorobis [(triphenylphosphine)-Palladium (II) (0.023 g, 0.003 mmol) was added and again degassed for 10 min. The reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. DMF was distilled off, after cooling to r.t., water was added into reaction mixture and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as yellow solid (0.050 g, 50%). 1H NMR (DMSO-d6, 400 MHz): δ 3.75 (s, 3H), 5.59 (s, 2H), 6.92 (d, 2H, J=8.8 Hz (o-coupling), 7.14 (dt, 1H, J=9.2 Hz (o-coupling), 7.36 (d, 2H, J=8.4 Hz (o-coupling), 7.45 (dt, 2H, J=9.2 Hz (o-coupling) J=5.2 Hz (o-coupling), 7.79 (m, 1H), 7.88 (broad s, 1H), 8.16 (broad s, 1H), 8.53 (d, 1H, J=2.0 Hz (m-coupling), 8.57 (d, 1H, J=4.8 Hz). MS ES+ (454.10), HPLC (method 5) Rt=15.26 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[N:10][CH:11]=1.O.C(Cl)(Cl)Cl>C(OCC)C>[N+:1]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[N:10]=[CH:11][C:6]([Cl:5])=[CH:7][N:8]=2)=[CH:14][C:15]=1[OH:19])([O-:4])=[O:2]
Reactant: Oc1cccc(Oc2ncc(Cl)cn2)c1
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(Oc2ncc(Cl)cn2)cc1O
Yield: 49.2 %

Procedure:
Fuming nitric acid (1.3 g) was added slowly to a stirred suspension of 3-(5-chloro-2-pyrimidyloxy)phenol (2.2 g) in diethyl ether (20 ml) at 20° C. The temperature rose to 30° C. and the resultant orange solution was allowed to stand for 48 hr before the addition of water and extraction with chloroform (100 ml). The chloroform extracts were dried and evaporated to give a pale yellow crystalline solid (1.3 g). Chromatography on a column of silica gel (80 g) with chloroform elution gave the title compound as a pale yellow-solid from the first fraction (0.7 g, 28%). The compound was identified from its pmr spectrum.
Reaction SMILES: CO.C([Cl:6])(C)=O.[CH2:7]([NH:14][CH2:15][CH:16]([CH3:31])[C:17]([C:19]1[C:20]([CH:28]([CH3:30])[CH3:29])=[N:21][N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=12)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[ClH:6].[CH2:7]([NH:14][CH2:15][CH:16]([CH3:31])[C:17]([C:19]1[C:20]([CH:28]([CH3:30])[CH3:29])=[N:21][N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=12)=[O:18])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)Cl
Agent: CC(CNCc1ccccc1)C(=O)c1c(C(C)C)nn2ccccc12
Solvent: CCOCC
Solvent: CO
Product: Cl
Reaction time: 0.17 h

Procedure:
To MeOH (2 mL) cooled in an ice bath under argon was added AcCl (0.047 mL) dropwise. This solution was stirred for 10 minutes before adding dropwise to 3-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one (0.200 g) in dry Et2O (5 mL), which was also cooled in an ice bath. The solvent was evaporated and the residue was treated with hexane (1 ml). the solvent was evaporated and a yellow solid was obtained. This solid was stirred in 10 mL of a solution containing MeOH (1%) and Et2O (99%) for 8 hours. The solid was filtered, washed with Et2O and dried under reduced pressure to afford 172 mg of 3-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one hydrochloride as a pale yellow solid. mp=171-175° C. (Et2O, pentane), IR (KBr) v=3428, 3034, 2965, 2784, 25589, 2425, 1642, 1538, 1507, 1481, 1440, 1360, 1264, 1210, 1188, 972; 1H NMR (600 MHz, DMSO-d6) δ=9.60 (bs, 1H), 9.23 (bs, 1H), 8.86 (d, J=6.8 Hz, 1H), 8.09 (d, J=9.1 Hz, 1H), 7.56-7.68 (m, 3H), 7.37-7.47 (m, 3H), 7.15 (tr, J=6.8 Hz, 1H), 4.15-4.23 (m, 2H), 3.87-3.95 (m, 1H), 3.74 (sept, J=6.8 Hz, 1H), 3.34-3.42 (m, 1H), 2.94-3.01 (m, 1H), 1.33 (d, J=6.8 Hz, 3H), 1.28 (d, J=6.8 Hz, 3H), 1.22 (d, J=7.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ=194.8, 164.4, 140.9, 132.3, 130.7, 130.6, 129.6, 129.4, 129.0, 118.7, 114.7, 107.4, 48.2, 41.3, 27.6, 22.9, 22.3, 17.1; MS (FAB) m/z 337 (M+1, 25.5), 336 (M+, 100.0), 218 (16.7), 217 (99.6), 187 (28.1), 173 (17.8), 161 (13.1), 120 (31.9); HRMS (FAB) calcd for C21H26N3O: 336.2076; found: 336.2066. Compound 1066.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5]>O1CCCC1>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1cccc(C(=O)O)c1F
Solvent: C1CCOC1
Product: COc1cccc(CO)c1F
Temperature: 25 °C
Reaction time: 4.2 h
Yield: 80.7 %

Procedure:
2-Fluoro-3-methoxybenzoic acid from Step 1 (16.65 g, 98 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), cooled in an ice bath, and treated with borane dimethyl sulfide complex (19 mL, 190 mmol). The reaction was stirred at room temperature for 4.2 hours, quenched by the slow addition of methanol, and concentrated in vacuo. The residue was dissolved in ethyl acetate, treated with 3N hydrochloric acid and filtered through diatomaceous earth. The organic layer of the filtrate was collected, washed with NaHCO3, brine, dried over MgSO4 and reconcentrated in vacuo to give 2-fluoro-3-methoxybenzyl alcohol (12.35 g, 81%) as a white solid: mp 53°-57° C.; 1H NMR (acetone-d6) 300 MHz 7.07 (m, 3H) 4.67 (d, J=5.8 Hz, 2H) 4.24 (t, J=5.8 Hz, 1H) 3.86 (s, 3H); 19F NMR (acetone-d6) 300 MHz -144.77 (m).