Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[C:11](Cl)[N:10]=1>>[Cl:8][C:9]1[N:10]=[C:11]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=[C:13]([I:15])[CH:14]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: NC1CCCCC1
Product: Clc1cc(I)cc(NC2CCCCC2)n1
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Cyclohexanamine (4.0 mL, 34.9 mmol) was added to 2,6-dichloro-4-iodo-pyridine (954 mg, 3.48 mmol) in a microwave tube and subjected to 300 watts at 150° C. for 30 minutes in a Biotage Microwave Reactor. The crude product was partitioned with water, dichloromethane and the organics combined and concentrated to dryness. The residue was partially purified using silica gel flash chromatography eluting with 2% ethyl acetate, 98% hexanes to give 916 mg 6-chloro-N-cyclohexyl-4-iodopyridin-2-amine as a purple gum. This material was dissolved in 15 mL DMF and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (666 mg, 1.98 mmol) added followed by addition of potassium acetate (400 mg, 4.07 mmol). The mixture was degassed with nitrogen and 1,1′-bis(diphenylphosphino)-ferrocene)dichloropalladium(II) complex with dichloromethane (222 mg, 0.272 mmol) added and the reaction mixture heated at 75° C. for 4 hours and then cooled to room temperature and partitioned with water, ethyl acetate. The organics were combined, concentrated to dryness and purified by silica gel flash chromatography eluting with a gradient from 3% ethyl acetate, 97% hexanes to 6% ethyl acetate, 94% hexanes to provide the title compound as a clear gum in 73% yield. MS (DCI+) m/z 337.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:11][P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14]>>[CH3:10][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH2:11][P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14]
Reactant: COC(=O)CCCC(C)C
Reactant: COP(C)(=O)OC
Product: COP(=O)(CC(=O)CCCC(C)C)OC

Procedure:
Dimethyl (6-methyl-2-oxoheptyl)phosphonate was prepared from methyl 5-methylcaproate and dimethyl methylphosphonate according to the known method.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:11][N:12]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH2:13][CH2:14][C:15]#[N:16]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CNCCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCC#N)c1ccc([N+](=O)[O-])cn1

Procedure:
2-Chloro-5-nitropyridine (158 mg, 1 mmol), 3-methylamino-propionitrile (84 mg, 1 mmol), and finely ground potassium carbonate (414 mg, 3 mmol) were heated to 80° C. in 10 mL anhydrous DMF for 3.5 hrs. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc layer was filtered, evaporated to dryness. ES-MS calcd for C9H10N4O2 (m/e) 206.21, obsd 207.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[N+:10]([CH:12](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:13])#[C-:11].C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:11]=[N:10][C:12]=2[CH3:13])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(Br)cn1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A mixture of 5-bromopicolinaldehyde (7.80 g, 41.9 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (8.78 g, 41.9 mmol), and K2CO3 (7.53 g, 54.5 mmol) in MeOH (150 mL) was heated at reflux for 3 hr. The reaction was then cooled to room temperature, the MeOH was evaporated at reduced pressure, and the crude material was partitioned between EtOAc and water. The separated aqueous layer was extracted twice with EtOAc. The combined organic extract was washed twice with water, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel (Analogix® SF65-600 column, 0% to 50% EtOAc/hexane) to afford 7.32 g (73%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.78 (dd, J=2.4, 0.6, 1H), 8.44 (s, 1H), 8.15 (dd, J=8.5, 2.4, 1H), 7.64 (dd, J=8.5, 0.6, 1H), 2.50 (s, 3H). MS (DCI+) m/z 239/241 (M+H).
Reaction SMILES: [NH4+].[Cl-].CC[N:5](CC)CC.[C:10]([O:14][C:15]([N:17]1[CH2:37][CH2:36][C:20]2([C:25]3=[CH:26][CH:27]=[CH:28][N:24]3[C:23]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=O)=[CH:32][C:22]=3[O:21]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:33]([C:31]1[CH:30]=[CH:29][C:23]2[N:24]3[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]3([CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:37][CH2:36]3)[O:21][C:22]=2[CH:32]=1)(=[O:35])[NH2:5]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(C(=O)O)ccc1-n1cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(C(N)=O)ccc1-n1cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A solution of NH4Cl (1.4 mL, 40 mmol) and Et3N (5.6 mL, 40 mmol) in DMF (6 mL) was added to a solution of 1-tert-butoxycarbonylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-carboxylic acid (3.1 g, 8.0 mmol), HATU (3.3 g, 8.8 mmol), and Et3N (2.5 mL, 18 mmol) in DMF (6 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and was washed with saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and evaporated. Purification of the residue by silica gel chromatography eluting with 0-100% EtOAc in Hexanes gave tert-butyl 7′-carbamoylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (2.7 g, 89%). ESI-MS m/z calc. 383.4, found 384.7 (M+1)+. Retention time: 1.60 minutes (3 min run).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25].[N+:27]([C:30]1[CH:34]=[N:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:31]=1[CH:43]=[O:44])([O-:29])=[O:28]>C(OCC)C.[Cl-].[NH4+].C(OCC)(=O)C.O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])[CH:43]([OH:44])[C:31]1[N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])[N:33]=[CH:34][C:30]=1[N+:27]([O-:29])=[O:28]
Reactant: C[Si](C)(C)CCOCn1ncc([N+](=O)[O-])c1C=O
Reactant: COC(=O)COc1ccc(F)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)C(Oc1ccc(F)cc1F)C(O)c1c([N+](=O)[O-])cnn1COCC[Si](C)(C)C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of diisopropylamine (0.3 mL, 2.1 eq) in diethyl ether (3 mL) was added a 2.5 M solution of n-butyllithium in hexanes (Aldrich) (0.84 mL, 2.1 eq). The resulting mixture was stirred for 15 minutes. To this mixture was added a solution of (2,4-difluorophenoxy)acetic acid methyl ester (425 mg, 2.1 eq) in diethyl ether (2 mL) via a syringe, and the resulting mixture was stirred at −78° C. for 30 minutes, after which a solution of 4-nitro-2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazole-3-carbaldehyde (271 mg, 1 mmol) in diethyl ether (2 mL) was added. The resulting mixture was stirred for 2 hours. The −78° C. reaction mixture was diluted with a saturated aqueous ammonium chloride solution, then diluted with ethyl acetate (150 mL) and water (25 mL). The organic layer was separated, washed with brine (1×50 mL), dried over magnesium sulfate, filtered and concentrated to give the crude product as an oil (709 mg). Purification of the crude product by Preparative Thin Layer Chromatography eluting with 25% ethyl acetate in hexanes gave the title compound as a diastereomeric mixture (257 mg, thick colorless oil). M+=473.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[CH:14]=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:14]=[O:15]
Reactant: BrCCc1ccccc1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCc2ccccc2)c(O)c1
Reaction time: 8 h

Procedure:
(2-Bromoethyl)benzene (20 mL, 0.14 mol, 2 eq) was added to a stirred solution of 3,4-dihydroxybenzaldehyde (10 g, 0.072 mol, 1 eq), tetra-n-butylammonium iodide (27 g, 0.072 mol, 1 eq) and cesium carbonate (14.2 g, 0.043 mol, 0.6 eq) in N,N-dimethylformamide (50 mL). The solution was stirred overnight, then concentrated in vacuo and diluted with ethyl acetate (200 mL). The organic solution was washed with 1M HCl (2×200 mL), and brine (200 mL), dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel, eluting with toluene:ethyl acetate (19:1). This gave the product as a colourless oil which crystallized on standing (2.71 g, 15%). RF (toluene:ethyl acetate, 9:1) 0.31. 1H NMR (CDCl3) δ 9.84 (s, 1H, O═C—H), 6.96 (d, 1H, J 8.3 Hz, ArH), 5.64 (s, 1H, OH), 4.36 (t, 2H, J 7.2 Hz, OCH2CH2Ph), 3.17 (t, 2H, J 7.2 Hz, OCH2CH2Ph).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.F>[Pd].C(O)C>[C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]c3ccccc23)cc1
Agent: [Pd]
Agent: F
Agent: FB(F)F
Solvent: CCO
Product: c1ccc(C2CNc3ccccc32)cc1
Reaction time: 18 h
Yield: 47 %

Procedure:
A mixture of 4.0 g of 3-phenylindole, 80 ml of 86% ethanol, 35 ml of 48% hydrofluoroboric acid and 0.25 g of 10% Pd/C was hydrogenated at 60 p.s.i. and 60° C. for 18 hours. The reaction mixture was worked up as in Example 2 and 1.9 g of pure 3-phenylindoline was obtained.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([Cl:20])=[CH:18][C:17]([C:21]([NH2:23])=O)=[CH:16][N:15]4[C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.CCCP(O)(O)=O.O>C(OCC)(=O)C>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:13]=[C:14]4[C:19]([Cl:20])=[CH:18][C:17]([C:21]#[N:23])=[CH:16][N:15]4[C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: NC(=O)c1cc(Cl)c2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2c1
Agent: CCCP(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)c2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A mixture of 2-[4-(1-aminocyclobutyl)phenyl]-8-chloro-3-phenylimidazo[1,2-a]pyridine-6-carboxamide (see example 6-1, 100 mg, 0.17 mmol, 72% purity) and 1-propylphosphonic acid cyclic anhydride as 50%-solution in ethyl acetate (0.21 ml, 0.35 mmol) in 1.35 ml ethyl acetate were stirred at room temperature overnight. The reaction mixture was hydrolysed with water and extracted with ethyl acetate. The organic phase was filtered through a Whatman filter and the volatile components were removed by rotary evaporation. The crude material was purified by column chromatography (Snap cartridge, dichloromethane/ethanol 95/5->dichloromethane/ethanol 7/3) to give 11 mg of the title compound (16% overall yield).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([N:11]2[CH:15]=[CH:14][N:13]=[N:12]2)[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:27][C:26]=2[F:35])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[F:35][C:26]1[CH:27]=[C:28]([C:31]([OH:34])([CH3:32])[CH3:33])[CH:29]=[CH:30][C:25]=1[C:19]1[S:18][C:17]([NH:16][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:11]3[CH:15]=[CH:14][N:13]=[N:12]3)[CH2:9][OH:10])[N:7]=2)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OCC(c1cccc(Br)n1)n1ccnn1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(CO)n4ccnn4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 2-(6-bromopyridin-2-yl)-2-(1H-1,2,3-triazol-1-yl)ethanol (110 mg, 0.41 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (120 mg, 0.41 mmol) according to the general procedure in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[N+:26]([O-])=O)(=[O:15])=[O:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[Sn]Cl>CCO>[NH2:26][C:17]1[CH:18]=[C:19]([C:22]([F:24])([F:23])[F:25])[CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:14])=[O:15]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 92.2 %

Procedure:
In a similar fashion using route 1 general procedure 4, N-(5-chloro-quinolin-8-yl)-2-nitro-4-trifluoromethyl-benzenesulfonamide (Intermediate 272) (0.7 g, 1.62 mmol), SnCl2 (0.92 g, 4.86 mmol) and EtOH (15 ml) gave the title compound (0.6 g, 92%) which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]#[N:9].[NH:16]1[CH2:21][CH2:20][C:19](=[N:22][OH:23])[CH2:18][CH2:17]1>C(O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:16]1[CH2:21][CH2:20][C:19](=[N:22][OH:23])[CH2:18][CH2:17]1)=[NH:9]
Reactant: N#CNc1ccccc1-c1ccccc1
Reactant: ON=C1CCNCC1
Solvent: CCO
Product: N=C(Nc1ccccc1-c1ccccc1)N1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-biphenylylcyanamide (3.9 g), 4-piperidone oxime (4.5 g) and ethanol (50 ml) was stirred at ambient temperature for 6 hours and then at 50°-60° C. for 5 hours to give a brown solid which was purified by chromatography on an aluminia column eluted successively with hexane, 1:4, 2:3, 3:2 and 4:1 mixtures of dichloromethane and hexane and the 99:1 mixture of dichloromethane and methanol to yield a solid which was recrystallised from ethyl acetate to give N-(2-biphenylyl)-4-hydroxyiminopiperidine-1-carboxamidine (m.p. 175°-176° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8](CC#N)[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1.[C:17]([OH:20])(=[O:19])[CH3:18].S(=O)(=O)(O)O.O1CCOCC1>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH2:18][C:17]([OH:20])=[O:19])[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc(CC#N)c(C)nc2c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2cc(CC(=O)O)c(C)nc2c1

Procedure:
Compounds of formula (50), wherein R4 and R5 are as defined in formula (I) and R6 is aryl or heteroaryl, can be prepared as described in Scheme 6. Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be prepared using the procedures described in Synthetic Comm., 17(14):1647-1653 (1987). Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be treated with a reducing agent, such as, but not limited to, lithium aluminum hydride or sodium borohydride, to provide (7-methoxy-2-methyl-3-quinolinyl)methanol. (7-Methoxy-2-methyl-3-quinolinyl)methanol can be treated with a chlorinating reagent, such as, but not limited to, thionyl chloride to provide 3-(chloromethyl)-7-methoxy-2-methylquinoline. 3-(Chloromethyl)-7-methoxy-2-methylquinoline can be treated with sodium cyanide or potassium cyanide to provide (7-methoxy-2-methyl-3-quinolinyl)acetonitrile. (7-Methoxy-2-methyl-3-quinolinyl)acetonitrile can be treated with acid, such as, but not limited to, glacial acetic acid and concentrated sulfuric acid, in water and 1,4-dioxane with heat to provide (7-methoxy-2-methyl-3-quinolinyl)acetic acid. (7-Methoxy-2-methyl-3-quinolinyl)acetic acid can be treated with a reducing agent, such as, but not limited to, B2H6, borane-THF complex, or borane-pyridine complex, to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethanol. 2-(7-Methoxy-2-methyl-3-quinolinyl)ethanol can be treated with methanesulfonyl chloride and a base, such as, but not limited to, triethylamine or diisopropylamine to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate. 2-(7-Methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate can be treated with an amine of formula (5) to provide amines of formula (47). Amines of formula (47) can be treated with BBr3 to provide hydroxy compounds of formula (48). Hydroxy compounds of formula (48) can be treated with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to provide triflates of formula (49). Triflates of formula (49) can be treated with boronic acids of formula (7) as described in Scheme 1 to provide compounds of formula (50).
Reaction SMILES: N#N.[CH:3](/[C:11]1[O:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1)=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>C(Cl)Cl.O>[Si:22]([O:17][CH2:16][C:14]1[N:15]=[C:11](/[CH:3]=[CH:4]/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:12][CH:13]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: OCc1coc(/C=C/c2ccccc2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: N#N
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (E)-(2-styryloxazol-4-yl)methanol (5.40 g, 26.8 mmol) in CH2Cl2 (56.0 mL) was treated at rt with tert-butylchlorodimethylsilane (8.52 g, 53.67 mmol) followed by imidazole (3.69 g, 53.67 mmol) and the resulting suspension was stirred for 1 h at rt. Water was added. The aq. layer was extracted with and the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (gradient from hept to 9:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (9:1 hept-EA)=0.35. LC-MS-conditions 07: tR=1.08 min, [M+H]+=316.13.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:30])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1)[CH3:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC>CCOC(C)=O>[CH2:23]([O:22][C:18]1[CH:17]=[C:16]([C:14]2([CH3:15])[C:3](=[O:2])[C:4]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][C:9]=3[Cl:10])[NH:12][C:13]2=[O:30])[CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1cccc(OCc2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(c2cccc(OCc3ccccc3)c2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Yield: 69.6 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 4,6-dichloro-2-[2-(3-benzyloxy-phenyl)-propionylamino]-benzoic acid methyl ester (2.80 g, 6.40 mmol) and LiHMDS (19.0 mmol, 1M THF solution). After normal workup, the objective compound (1.90 g, 71%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=9:1): 1H NMR (200 MHz, DMSO-d6) δ 1.55 (s, 3H, CH3), 5.02 (s, 2H, OCH2), 6.69-7.02 (m, 2H, ArH), 7.22-7.38 (m, 7H, ArH), 11.28 (br s, 1H, NH); m.p. 201-203° C.; MS(EI) m/e 426 [M++1], 160, 91.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[CH:12]([S:15]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])(=[O:17])=[O:16])([CH3:14])[CH3:13].[H-].[Na+].CCCCCC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([C:9]#[N:10])=[C:6]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[S:15]([CH:12]([CH3:14])[CH3:13])(=[O:17])=[O:16])[N:7]=1
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C#N
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of 2,4,6-trichloropyrimidine-5-carbonitrile (1.0 mmol) and 2-(isopropylsulfonyl)aniline (1.0 mmol) in 5 mL of DMF, was added sodium hydride (24 mg). The suspension was stirred at 30° C. for 2 hours. Product was obtained after work-up and column chromatography (9:1 Hexane:EtOAc). MS (ES+): 371.01 (M+1)+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH2:12][CH3:13])[CH:6]=1)C.[NH3:15]>CO>[CH2:12]([C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH3:11])[N:8]=1)[C:4]([NH2:15])=[O:3])[CH3:13]
Reactant: CCOC(=O)c1cc(C)nc(CC)c1
Reactant: N
Solvent: CO
Product: CCc1cc(C(N)=O)cc(C)n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of 2-ethyl-6-methyl-isonicotinic acid ethyl ester (3.90 g, 20.2 mmol, prepared in analogy to the corresponding tert.-butyl ester) in 7 N NH3 in methanol (50 mL) is stirred in a sealed vessel at 60° C. for 20 h. The solvent is evaporated and the residue is suspended in diethyl ether. The solid material is collected, washed with additional diethyl ether and dried under HV to give 2-ethyl-6-methyl-isonicotinamide (2.85 g) as a white powder; LC-MS: tR=0.26 min, [M+1]+=165.05; 1H NMR (D6-DMSO): δ 1.23 (t, J=7.5 Hz, 3H), 2.49 (s, 3H), 2.75 (q, J=7.8 Hz, 2H), 7.44 (s, 2H), 7.59 (s br, 1H), 8.11 (s br, 1H).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([Cl:19])[C:11]=1[Cl:20])[CH2:5][C:6]([OH:8])=[O:7])[CH3:3].C1C2N=C3N(CC=2C(Cl)=C(Cl)C=1)CC(=O)N3.Cl[Sn]Cl.Cl>>[ClH:19].[CH2:2]([N:4]([CH2:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([Cl:19])[C:11]=1[Cl:20])[CH2:5][C:6]([OH:8])=[O:7])[CH3:3]
Reactant: CCN(CC(=O)O)Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C1CN2Cc3c(ccc(Cl)c3Cl)N=C2N1
Product: CCN(CC(=O)O)Cc1c(N)ccc(Cl)c1Cl

Procedure:
The ethyl-N-(2,3-dichloro-6-nitro benzyl) glycine HCl prepared above was used to make Anagrelide by known reactions. Firstly, the ethyl-N-(2,3-dichloro-6-nitro benzyl) glycine HCl is reacted with SnCl2 /HCl to form ethyl-N-(2,3-dichloro-6-amino benzyl) glycine HCl. This material is then reacted with CNBr in an inert, aprotic organic solvent such as toluene or chlorobenzene. The formed ethyl-N-(5,6-dichloro-3,4-dihydro-2(1 H) iminoguinazoline-3-acetate HCl is isolated and then reacted with a base such as triethanolamine (TEA) to form Anagrelide. This synthesis process is shown in U.S. Pat. No. 4,146,718, supra. The Anagrelide product produced had the characteristic pharmaceutical properties of commercially available Anagrelide made using for example, the present prior art synthesis process as described above.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:19][CH3:20])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(O)c(OC)c1
Yield: 90 %

Procedure:
A mixture of (4-hydroxy-3-methoxyphenyl)acetic acid (15.00 g), conc. sulfuric acid (5 mL) and anhydrous ethanol (100 mL) was heated under reflux for 17 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:9 to 7:3, v/v) to give ethyl (4-hydroxy-3-methoxyphenyl)acetate as a colorless oil (14.55 g, yield 90%).