Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=2)[NH:8][N:7]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[C:14]=23)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: ClCCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: C1COCCN1
Product: Clc1cc(Nc2ncnc3[nH]nc(OCCCN4CCOCC4)c23)ccc1OCc1ccccn1
Yield: 30 %

Procedure:
The procedure described in Example 23 was repeated using 3-(3-chloropropoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and morpholine to give the title compound in 30% yield; NMR Spectrum: 1.95-2.01 (m, 2H), 2.36 (br s, 4H), 2.44 (t, 2H), 3.55 (br s, 4H), 4.35 (t, 2H), 5.29 (s, 2H), 7.24 (d, 1H), 7.36-7.38 (m, 1H), 7.54-7.58 (m, 2H), 7.87-7.89 (m, 2H), 8.27 (s, 1H), 8.44 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=[O:4].[Na].[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]([C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2CBr)[CH:15]=1.[OH-].[K+]>O>[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]([C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:8][CH:2]([CH3:1])[C:3]([OH:5])=[O:4])[CH:15]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1ccccc1-c1cnc2ccccc2c1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CC(Cc1ccccc1-c1cnc2ccccc2c1)C(=O)O
Temperature: 130 °C

Procedure:
104 g (0.6 mol) of diethyl methylmalonate were added dropwise at room temperature to 13.8 g (0.6 mol) of sodium in 300 cm3 of H2 O-free EtOH. Subsequently, 178 g (0.6 mol) of 2-(3-quinolyl)benzyl bromide were added dropwise and the mixture was heated under reflux for 3 hours. At room temperature, 100 g (1.8 mol) of KOH dissolved in 400 cm3 of H2O were added and the mixture was heated under reflux for a further 4 hours. The EtOH was distilled off and the residue was admixed with H2O until completely dissolved and subsequently acidified with concentrated aqueous HCl to a pH of 1. The precipitate formed was filtered off with suction, dried and heated for 1 hour at 130° C. This gave 145 g (83%) of 2-(2-(3-quinolyl)benzyl)propionic acid as solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=2[C:25]2[O:26][C:27](=[O:35])[C:28]3[CH:34]=[CH:33][N:32]=[CH:31][C:29]=3[N:30]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-]#N.[K+].[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([NH2:46])=[N:44][CH:45]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:22])[CH3:23])[CH:18]=[CH:17][C:16]=2[C:25]([NH:30][C:29]2[CH:31]=[N:32][CH:33]=[CH:34][C:28]=2[C:27]([NH:46][C:43]2[CH:42]=[CH:41][C:40]([Cl:39])=[CH:45][N:44]=2)=[O:35])=[O:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2-c2nc3cnccc3c(=O)o2)CC1
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2cnccc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 70 °C
Yield: 23.5 %

Procedure:
A mixture of 2-[2-(1-tert-butoxycarbonylpiperidin-4-yl-oxy)-4-tert-butylphenyl]-4H-pyrido[3,4-d][1,3]oxazin-4-one (100 mg, 0.21 mmol), KCN (100 mg), 5-chloro-2-aminopyridine (53 mg, 0.42 mmol), and dry DMF (2 mL) was heated at 70° C. for 4 h, then quenched with brine (25 mL). The mixture was extracted with 10% MQOH in EtOAc (2×20 mL), and the combined extracts were washed with brine (3×100 mL) then dried over MgSO4. After filtering, the filtrate was concentrated to an oil which was purified by chromatography using 60% EtOAc in hexanes to give 30 mg of an oil which crystallized.
Reaction SMILES: [ClH:1].[CH3:2][C@H:3]1[N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C@@H:7]([CH3:23])[C:6]2[S:24][CH:25]=[CH:26][C:5]=2[CH2:4]1.[Br:27]Br>>[ClH:1].[Br:27][C:25]1[S:24][C:6]2[C@H:7]([CH3:23])[N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:22])[C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C@H:3]([CH3:2])[CH2:4][C:5]=2[CH:26]=1
Reactant: BrBr
Reactant: C[C@@H]1Cc2ccsc2[C@H](C)N1CCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: C[C@@H]1Cc2cc(Br)sc2[C@H](C)N1CCNC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
The thiophene compound from Example 28 (2.5 g, 6.96 mmol) was treated with bromine (0.71 mL, 14 mmol) as described for Example 75. The title compound was isolated (1.31 g, 43%) and treated with HCl/2-propanol (1.1 eq) to afford a brown solid; mp 265°-267° C.; IR (KBr) 3260 2480, 1665, 1600, 1550, 1525, 1340, 1290, 1105, 1110, 865, 855, 825 and 715 cm-1.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][C:12]([CH3:25])([O:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH3:13]>CCCCCC.O1CCCC1>[CH3:13][C:12]([CH3:25])([O:14][C:15]([NH:17][C@@H:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[CH:23]([C:7]1[S:6][CH:10]=[CH:9][N:8]=1)[OH:24])=[O:16])[CH3:11]
Reactant: c1cscn1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)c1nccs1
Reaction time: 0.58 h

Procedure:
2.5 n-Butyllithium in hexane (8 ml.) is added to a solution containing thiazole (1.7 g., 20 mmole) in dry tetrahydrofuran (60 ml.) cooled to -70° under argon. After stirring a short time, the solid material begins to come out of solution. The reaction remains heterogeneous after 35 minutes at -40° to -35° . After cooling the reaction to -50° , a solution containing N-[(1,1-dimethylethoxy)carbonyl]-L-leucinal (2.2g., 10 mmole) in tetrahydrofuran (5 ml.) is added. After 90 minutes the reaction is warmed to -10° and quenched with saturated ammonium chloride (10 ml.). The reaction mixture is extracted into ether and the organic extract is rinsed with water and brine, dired (MgSO4) and concentrated in vacuo to give 1.8 g. of amide product. Two flash chromatographies on first 100 g. and then 150 g. of silica gel (LPS-1) eluting with petroleum ether:acetone (20:1 ) fails to remove a minor impurity from the co-eluting desired diastereimeric product mixture. A total of 1.2 g. of (2S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-methyl-1-(2-thiazolyl)-1-pentanol is obtained. TLC (silica gel; petroleum ether:acetone, 4:1) Rf =0.37. 8 α]D =-38.6° (c=1, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([C:21](OC)=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7].[BH4-].[Li+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([CH2:21][OH:22])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13]1)=[O:7]
Reactant: COC(=O)C1(C(=O)NCc2ccccc2Cl)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)(C(=O)NCc2ccccc2Cl)CC1
Yield: 84.5 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-(2-chlorobenzylcarbamoyl)piperidine-1,4-dicarboxylate (2.8 g, 6.8 mmol) in THF (20 mL) and CH3OH (10 mL) was added lithium borohydride (1.4 g, 68 mmol, 10 equiv.). The reaction mixture was stirred for 3 h and neutralized with HCl (1N). The residue was partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4 and concentrated to purify on RP-HPLC using a mixture of acetonitrile and H2O to give tert-butyl 4-(2-chlorobenzylcarbamoyl)-4-(hydroxymethyl)piperidine-1-carboxylate (2.2 g, 84%). LRMS (M-tBu+H+) m/z 327.0.
Reaction SMILES: NCCN[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[NH2:22][CH2:23][C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[C:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@@H:24]1[CH2:23][NH:22][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using (R)-2-(aminomethyl)-1-N-BOC-pyrrolidine instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 442 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.48 (1H, br. s.) 10.24 (1H, br. s.) 8.17 (1H, br. s.) 8.02 (1H, d, J=5.47 Hz) 7.79 (1H, d, J=5.27 Hz) 7.44-7.54 (1H, m) 7.31 (1H, d, J=2.73 Hz) 6.82 (1H, br. s.) 6.41 (1H, br. s.) 3.93 (1H, br. s.) 3.39 (1H, br. s.) 3.23 (2H, br.s.) 1.67-1.88 (4H, m) 1.39 (9H, s)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:36]4[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:42])[F:43])=[CH:38][CH:37]=4)[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2ccc(OC(F)(F)F)cc2)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and 4-trifluoromethoxyphenyl boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (DMSO-d6) δ 10.4(s, 1H), 8.4(s, 1H), 8.2(m, 1H), 8.05(d, 1H, J=7.2 Hz), 7.9(m, 3H), 7.4-7.7(m, 7H), 7.0(d, 1H, J=10.1 Hz), 4.3(m, 2H), 3.6(m, 4H), 2.9(m, 2H), 2.6(m, 4H).
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.[F:6][C:7]([F:18])([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH2:8]CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.CC(=O)OCC>C(Cl)Cl.O>[Br:5][CH2:2][CH2:8][C:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([F:6])[F:18]
Reactant: BrC(Br)(Br)Br
Reactant: OCCC(F)(F)c1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(C(F)(F)CCBr)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
3.1 g (9.5 mmol) of tetrabromomethane were added to a solution of 1.0 g (5.3 mmol) of 3,3-difluoro-3-(4-fluorophenyl)propan-1-ol in DCM (20 ml) and cooled to 0° C. At that temperature, 2.48 g (9.5 mmol) of triphenylphosphine were added in portions. Stirring was then carried out for 3 h at RT. The mixture was then diluted with water (50 ml) and extracted with EA (3×60 ml). The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 24:1) of the residue yielded 1.25 g (5.0 mmol, 94%) of 1-(3-bromo-1,1-difluoropropyl)-4-fluorobenzene.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccc(-c2cc(C(F)(F)F)ccn2)cc1
Temperature: 100 °C
Yield: 99.3 %

Procedure:
To a mixture of 2-chloro-4-(trifluoromethyl)pyridine (19.9 g, 0.11 mol), 4-(methylthio)phenylboronic acid (21.9 g, 0.13 mol), 1M aqueous sodium carbonate (180 mL) and 1,2-dimethoxyethane (270 mL) under an atmosphere of nitrogen was added palladium tetrakistriphenylphosphine (3.78 g, 3.3 mmol) and the reaction heated at 100° C. for 14 hours. After cooling and concentration in vacuo, the residue was partitioned between ethyl acetate (350 mL) and water (400 mL) and separated. The aqueous layer was further extracted with ethyl acetate (2×150 mL) and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Filtration through a pad of silica gel (200 g) eluting with a gradient of ethyl acetate in cyclohexane gave the title compound (29.4 g) LC retention time 3.62 mins, MS m/z 269 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=[C:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([CH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(C2CCC(=CC(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(C2CCC(CC(=O)OC(C)(C)C)CC2)cc1
Yield: 85 %

Procedure:
5.04 g of ethyl 4-(4-tert-butoxycarbonylmethylenecyclohexyl)benzoate (14.63 mmol, 1 eq.) and 15 mL of ethanol are placed in a Parr bottle. 0.31 g of 10% palladium-on-charcoal (0.29 mmol, 0.02 eq.) is added and the reaction medium is placed under 50 psi of hydrogen for 3 hours at a temperature of 25° C. The reaction medium is filtered and concentrated to give 4.31 g of ethyl 4-(4-tert-butoxycarbonylmethylcyclohexyl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@@H:13]([C:17]([OH:19])=[O:18])[C@H:14]([CH3:16])[OH:15].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:12][C@H:13]([C@@H:14]([OH:15])[CH3:16])[C:17]([OH:19])=[O:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 75 °C
Reaction time: 24 h

Procedure:
2-chloro-4-fluoro-3-methylbenzonitrile (CAS 796600-15-2, 45 g, 265.4 mmol) was mixed together with H-D-Thr-OH (37.92 g, 318.4 mmol) in DMSO (250 mL). K2CO3 (73.35 g, 530.7 mmol) was added to the reaction mixture and the reaction mixture stirred at 75° C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed on silica gel with a gradient of hexanes/EtOAc and then with EtOAc, 100% to get the purified final product (39.0 g, 54%) 1H NMR (500 MHz, Acetone-d6, δ in ppm) 7.49 (d, J=9 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 5.38 (d, J=10 Hz, 1H), 4.47 (d, J=6 Hz, 1H), 4.25 (m, 1H), 2.34 (s, 3H), 1.33 (d, J=6 Hz, 3H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:29])[CH2:4][CH:5]([OH:28])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24]COC)[CH:19]=1>O1CCOCC1.C(Cl)Cl>[ClH:1].[CH3:29][N:3]([CH3:2])[CH2:4][CH:5]([OH:28])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1
Reactant: COCOc1cccc(CCCCc2ccccc2OCC(O)CN(C)C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)CC(O)COc1ccccc1CCCCc1cccc(O)c1
Reaction time: 0.25 h
Yield: 89 %

Procedure:
5 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 1.00 g of 3-dimethylamino-1-{2-[4-(3-methoxymethoxyphenyl)butyl]phenoxy}-2-propanol [prepared as described in step (b) above] in 10 ml of methylene chloride, and the resulting mixture was allowed to stand at room temperature for 15 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was dissolved in ethyl acetate and then allowed to stand. The crystals which precipitated were collected by filtration and dried in vacuo, to give 0.87 g (yield 89%) of the title compound as colorless crystals, melting at 124°-125° C.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1>C(#N)C.C(OCC)(=O)C.[Cu](Br)Br>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH3:21]
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: Br[Cu]Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 7 h

Procedure:
8.3 g (27.2 mmol) of 11β-fluoro-7α-methylestr-4-ene-3,17-dione in 260 ml of acetonitrile is mixed with 7.0 g (31.3 mmol) of copper(II) bromide, and the reaction mixture is stirred for 7 hours at room temperature. For working-up, the reaction solution is diluted with ethyl acetate, the organic phase is washed with aqueous ammonium chloride solution, sodium bicarbonate solution, and finally with water and dried on sodium sulfate. The crude product is chromatographed on silica gel (toluene-ethyl acetate, gradient of up to 7:3), yield 3.3 g (40%), [α]D+166.80 (c 0.5 methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:39]=[CH:38][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[N:14]=[C:15]([N:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[C:8]=23)=[C:4]([F:40])[CH:3]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH:52]3[C:50]([C:54](O)=[O:55])([CH2:51]3)[C:49]2=[O:57])=[CH:44][CH:43]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:13]2[C:9]3=[N:10][CH:11]=[CH:12][C:7]([O:6][C:5]4[CH:38]=[CH:39][C:2]([NH:1][C:54]([C:50]56[CH2:51][CH:52]5[CH2:53][N:48]([C:45]5[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=5)[C:49]6=[O:57])=[O:55])=[CH:3][C:4]=4[F:40])=[C:8]3[C:15]([N:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:20][CH2:21]3)=[N:14]2)=[CH:31][CH:32]=1
Reactant: COc1ccc(Cn2nc(N3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)C12CC1CN(c1ccc(F)cc1)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(N3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)C56CC5CN(c5ccc(F)cc5)C6=O)cc4F)ccnc32)cc1
Yield: 71.7 %

Procedure:
A solution of tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.182 mmol, obtained from Example 82 Step A), 3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (85.7 mg, 0.365 mmol, obtained from Example 98 Step D), EDCI (210 mg, 1.09 mmol) and HOBT (148 mg, 1.09 mmol) was stirred in DMF (6 mL) for 12 hours. The reaction mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, 10% aqueous LiCl, dry with Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (5% MeOH in CH2Cl2) to afford the product (100 mg, 71.6% yield) as a white solid. LRMS (APCI pos) m/e 766.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH2:7][CH2:6][O:5][C:4]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)#[N:2].[I-].[Na+]>CN(C)C=O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([N:8]2[CH2:6][CH2:7][CH:3]([C:1]#[N:2])[C:4]2=[O:5])=[O:17])=[CH:11][CH:12]=1
Reactant: N#CC1=C(NC(=O)c2ccc(F)cc2)OCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1CCN(C(=O)c2ccc(F)cc2)C1=O
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of N-(3-cyano-4,5-dihydrofuran-2-yl)-4-fluorobenzamide (5.0 g) obtained in Step E in N,N-dimethylformamide (30 mL) was added sodium iodide (6.5 g), and the mixture was stirred at 150° C. for 30 min. The solvent was evaporated under reduced pressure, and to the residue was added ice water. The resulting solid was collected by filtration, and washed with water. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the resulting solid was washed with diisopropyl ether to give the title compound (1.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](Br)[C:11]=1[CH2:12][O:13][C:14]([NH:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[O:15])[C:5]([O:7][CH3:8])=[O:6].C(N(C(C)C)CC)(C)C>CN(C=O)C.[Cu]I>[Br:1][C:2]1[C:11]2[CH2:12][O:13][C:14](=[O:15])[N:16]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[C:10]=2[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1
Reactant: COC(=O)c1cc(Br)c(COC(=O)Nc2c(Cl)cccc2Cl)c(Br)c1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)OC2

Procedure:
To a solution of methyl 3,5-dibromo-4-[({[(2,6-dichlorophenyl)amino]carbonyl}oxy)methyl]benzoate (1 g, 1.96 mmol, 1 eq) in DMF (20 mL) was added CuI (411 mg, 2.16 mmol, 1.1 eq) and diisopropylethylamine (0.51 mL, 2.95 mmol, 1.5 eq). Degassed the reaction flask with argon and placed in a 140° C. oil bath. After 2.5 h the reaction was cooled. The mixture was filtered to remove inorganics. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2, and washed with water. The aqueous layer was back-extracted 2× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated. The residue was triturated with Et2O leaving 283 mg of solid methyl 5-bromo-1-(2,6-dichlorophenyl)-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-7-carboxylate. The supernatant was further purified by flash column chromatography on silica gel eluting with 2:1 CH2Cl2/hexanes giving an additional 309 mg of not quite pure product. Mass spectrum (ESI) 430.0 (M+1); 432.0 (M+3), 434.0 (M+5).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>O>[Cl:12][C:4]1[N:3]=[C:2]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH3:13])[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[CH:5]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)cc21
Reactant: COc1ccc(CN)c(OC)c1
Solvent: O
Product: COc1ccc(CNc2nc(Cl)cc3c2ncn3C)c(OC)c1
Temperature: 110 °C
Yield: 95 %

Procedure:
In a 200 mL round bottom flask, 4,6-dichloro-1-methyl-1H-imidazo[4,5-c]pyridine (15 g, 74.2 mmol) (prepared as per WO2006122137 example A1.5) was dissolved in 2,4-dimethoxybenzylamine (25 mL, 166 mmol). The reaction mixture was heated to 110° C. for 3 h and cooled to room temperature. Water was added and a tan colored solid precipitated out. Vacuum filtration yielded a tan solid. The solid was washed with ethyl acetate and hexane to yield 6-chloro-N-(2,4-dimethoxybenzyl)-1-methyl-1H-imidazo[4,5-c]pyridin-4-amine (23.459 g, 95% yield) as a cream colored solid.
Reaction SMILES: C(C(NC(C1C=C(C)C=CC=1S[S:20][N:21]([C:30](=[O:38])[C:31]1[CH:36]=[C:35](C)[CH:34]=[CH:33][CH:32]=1)[CH:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=O)CC(C)C)(O)=O.BrBr.[C:41](#N)C>ClCCl>[CH3:29][CH:27]([CH3:28])[CH2:26][C@H:22]([N:21]1[C:30](=[O:38])[C:31]2[CH:32]=[CH:33][C:34]([CH3:41])=[CH:35][C:36]=2[S:20]1)[C:23]([OH:25])=[O:24]
Reactant: Cc1cccc(C(=O)N(SSc2ccc(C)cc2C(=O)NC(CC(C)C)C(=O)O)C(CC(C)C)C(=O)O)c1
Reactant: CC#N
Agent: BrBr
Solvent: ClCCl
Product: Cc1ccc2c(=O)n([C@@H](CC(C)C)C(=O)O)sc2c1

Procedure:
Following the general method of Example 3, a slurry of [s-(R*,R*)]-2-[-[2-(1-carboxy-3-methylbutylcarbamoyl)-4-methylphenyldisulfanyl]-5-methylbenzoylamino]-4-methyl-pentanoic acid (1.8 g, 3.2 mmol) (from Preparation 22) in 5 mL acetonitrile and 20 mL dichloromethane was reacted with bromine (0.6 g, 3.7 mmol) in 10 mL dichloromethane. The crude product was recrystallized from methanol/water to afford 1.3 g of the title compound.