Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)C1C=C[C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.C(Cl)(=O)C(Cl)=[O:35].CNC(N)=O.N1C=CC=CC=1>ClC1C=CC=CC=1.CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[S:13][CH2:12][C:11]([NH:10][C:7]([NH:6][CH3:5])=[O:35])=[O:31])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CNC(N)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: CNC(=O)NC(=O)CSC1C(C)=C(C)C(=O)N1Cc1ccc(OC)cc1
Reaction time: 1 h
Yield: 55 %

Procedure:
The product from Example 1, Part C (200 mg, 0.6 mmol) was dissolved in 3 mL chlorobenzene and 2 drops DMF, then cooled to 0° C. Oxalyl chloride (0.72 mL, 2 M in CH2Cl2) was added and the mixture was stirred for 1 h while the temperature rose to room temperature. Methyl urea (133 mg, 1.2 mmol) was added and the mixture was stirred at 70° C. for 10 min. pyridine (0.12 mL, 1.2 mmol) was added and the mixture was stirred at 70° C. for 0.5 h. The reaction solvent was evaporated and the product was purified by silica gel chromatography. Recrystallization from CH2Cl2/ether provided the title compound as a white solid (130 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 9.98 (br s, 1H), 8.21 (br s, 1H), 7.20 (d, J=8 Hz, 2H), 6.83 (d, J=8 Hz, 2H), 50.8 (d, J=15 Hz, 1H), 4.57 (s, 1H), 4.14 (d, J=15 Hz, 1H), 3.77 (s, 3H), 2.89 (m, 5H), 1.95 (s, 3H), 1.84 (s, 3H). MS: m/z (MH+) 378.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:9]=[C:8]2[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)=[N+]=[N-]>C(O)C.O1CCCC1.C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-]>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:9]=[C:8]2[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CN=[N+]=[N-])ccc21
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CN)ccc21
Reaction time: 1.5 h
Yield: 83.5 %

Procedure:
To a solution of 550 mg of tert-butyl 5-(azidomethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate in a mixture of 10 ml ethanol and 5 ml tetrahydrofuran was added 110 mg of 5% palladium-calcium carbonate, and the mixture was hydrogenated at room temperature at normal pressure for 1.5 hours. After filtering off the catalyst through Celite, the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:methanol=1:0 to 9:1), to give 427 mg of the title compound as light green crystals.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C>C1(C)C=CC=CC=1>[CH:1]1([N:4]2[CH2:5][CH2:6][CH:7]([C:10]3[CH:11]=[CH:12][C:13]([C:14]([NH:37][C:34]4[NH:35][N:36]=[C:32]([CH2:31][CH2:30][C:24]5[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=5)[CH:33]=4)=[O:16])=[CH:18][CH:19]=3)[CH2:8][CH2:9]2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(C2CCN(C3CC3)CC2)cc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(C4CCN(C5CC5)CC4)cc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Yield: 35.8 %

Procedure:
Methyl 4-(1-cyclopropylpiperidin-4-yl)benzoate (0.259 g, 1 mmol), 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1.00 mmol) in toluene (10 ml) was treated with a 2M solution of trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, under nitrogen. The reaction mixture was heated at 60° C. for 18 h. The reaction mixture was cooled and the reaction quenched with methanol (40 ml) and acidified with 2N HCl (1 ml). The crude reaction mixture was purified by ion exchange chromatography, using an SCX column. The crude product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/methanol in DCM. Pure fractions were evaporated to dryness and the product crystallised from DCM/diethyl ether to give the title compound (0.170 g, 35.8%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16].Cl.[CH3:19][C:20]1([NH2:23])[CH2:22][CH2:21]1.C(N(CC)CC)C>CS(C)=O.O>[Br:1][C:2]1[C:3]([F:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:23][C:20]1([CH3:19])[CH2:22][CH2:21]1)[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16]
Reactant: O=c1c2ccc(F)c(Br)c2nc(Cl)n1C1CC1
Reactant: CC1(N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC1(Nc2nc3c(Br)c(F)ccc3c(=O)n2C2CC2)CC1
Temperature: 100 °C
Yield: 69.2 %

Procedure:
A glass microwave reaction vessel was charged with 8-bromo-2-chloro-3-cyclopropyl-7-fluoroquinazolin-4(3H)-one (721) (125 mg, 0.394 mmol) and 1-methylcyclopropanamine hydrochloride (127 mg, 1.18 mmol, Small Molecules Inc.) in DMSO (1.0 mL) followed by triethylamine (0.16 mL, 1.18 mmol). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL×4). The combined organic layers were washed with water (15 mL), dried (MgSO4), filtered and concentrated. The residue was triturated with hexanes and filtered to give the crude product 96 mg. MS (ESI, pos. ion) m/z: 352 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (1H, dd, J=8.8, 6.1 Hz), 6.90 (1H, t, J=8.4 Hz), 2.65-2.74 (1H, m), 1.61 (3H, s), 1.30-1.37 (2H, m), 0.83-0.96 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([S:10]([NH2:13])(=[O:11])=[O:12])=[C:2]([NH:1][S:24](/[CH:23]=[CH:22]/[C:17]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=2)(=[O:26])=[O:25])[CH:7]=1)#[N:9]
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1ccc(S(N)(=O)=O)c(N)c1
Product: N#Cc1ccc(S(N)(=O)=O)c(NS(=O)(=O)/C=C/c2ccc(Cl)c(Cl)c2)c1
Yield: 57 %

Procedure:
The title compound was synthesized as described for Example 178 in 57% yield, starting from 2-amino-4-cyanobenzenesulfonamide and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride.
Reaction SMILES: CS(CCNCC1OC([C:14]2[CH:15]=[CH:16][C:17]3[N:23]=C[N:21]=[C:20](NC4C=CC(OCC5C=CC=C(F)C=5)=C(Cl)C=4)[C:18]=3[CH:19]=2)=CC=1)(=O)=O.NC1C=CC=CC=1C#N.[I:50]I.ICl>>[NH2:23][C:17]1[CH:16]=[CH:15][C:14]([I:50])=[CH:19][C:18]=1[C:20]#[N:21]
Reactant: II
Reactant: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: ClI
Agent: N#Cc1ccccc1N
Product: N#Cc1cc(I)ccc1N

Procedure:
Accordingly, the basic raw material selected for the synthesis of Lapatinib of formula-(1) is commercially available 2-amino benzonitrile of formula-(6), which reacts with iodine or iodinemonochloride to get 2-amino-5-iodobenzonitrile of the formula-(7). The compound of the formula-(7) on reaction with a novel compound N1-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-N,N-dimethylformamidine (8) at elevated temperature gives the compound N-[3-chloro-4-[(3-fluorobenzyloxy)phenyl]-6-iodo-quinazolinamine of formula-(3), The compound of the formula-(3) on reaction with 5-formyl-2-furyl boronic acid, in presence of triethylamine and Pd/C gives the compound 5-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-quinazolinyl)-furan-2-carbaldehyde of the formula-(4). The compound of the formula-(4), on reaction with 2-methanesulfonylethylamine hydrochloride gives the novel compound N[3-chloro-4[(3-fluorobenzyloxy]phenyl[-6-[5-({[2-methanesulphonyl)-ethyl]imino}-2-furyl]-4-quinazolinamine of the formula-(9). The novel imine compound of formula-(9) on reduction, using sodium borohydride gives the compound of the formula-(1), which is Lapatinib base. The reaction scheme of the present invention is as given the following Scheme-(C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2ccc(Cl)cc2)cc1
Yield: 26.2 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(4-chlorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.075 g; 0.216 mmol), 4-chlorophenylboronic acid (0.035 g; 0.227 mmol), tetrakis(triphenylphosphine)palladium(0) (0.013 g; 0.011 mmol), sodium carbonate (0.046 g; 0.432 mmol), sodium iodide (0.065 g; 0.432 mmol), in dimethoxyethane (3 mL) and water (1 mL), heated in a sealed tube at 130° C. for 18 hours. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.024 g (27%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1([F:42])[CH2:3][CH2:4][N:5]([C:28]([C:30]2[S:34][C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:32][C:31]=2[CH3:41])=[O:29])[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([O:21]CC)=[O:20])[CH2:14][CH2:13]1)=[O:11].[OH-].[Na+]>C(O)C>[F:42][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:28]([C:30]2[S:34][C:33]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[N:32][C:31]=2[CH3:41])=[O:29])[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][CH2:17]1)=[O:11]
Reactant: CCOC(=O)CC1CCN(C(=O)/C=C2/c3ccccc3N(C(=O)c3sc(-c4ccccc4)nc3C)CCC2(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(CC(=O)O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution of 150 mg of ethyl (Z)-(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}-4-piperidyl)acetate in 5 ml of ethanol was added 1 ml of a 1N aqueous solution of sodium hydroxide, followed by stirring at room temperature for 18 hours. After evaporating off the reaction solution, 1 ml of 1N hydrochloric acid was added to the residue, and the resulting precipitate was collected by filtration and washed with water to give 120 mg of (Z)-(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}-4-piperidyl)acetic acid as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([C:26]1[CH:30]=[C:29]([CH2:31]Br)[O:28][C:27]=1[C:33]([F:36])([F:35])[F:34])=[O:25])[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:31][C:29]2[O:28][C:27]([C:33]([F:35])([F:36])[F:34])=[C:26]([C:24]([O:23][CH2:21][CH3:22])=[O:25])[CH:30]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Reactant: CCOC(=O)c1cc(CBr)oc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(COc2ccc(Cl)cc2OC2CN(C(=O)OC(C)(C)C)C2)oc1C(F)(F)F
Yield: 71.2 %

Procedure:
The title compound was prepared as described in Example 1 Step D using 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.3 g, 1.0 mmol), the title compound of Example 75 Step A (0.75 g, 2.5 mmol), Cs2CO3 (0.80 g, 2.4 mmol) and KI (0.23 g, 1.4 mmol) in DMF (15 mL). The crude material was purified by RP HPLC to provide the title compound (0.37 g, 71%). 1H NMR (CDCl3): 7.20-6.92 (m, 1H), 6.91-6.80 (m, 2H), 6.77-6.69 (m, 1H), 6.53 (d, J=2.1 Hz, 1H), 4.87 (s, 2H), 4.79-4.69 (m, 1H), 4.27-4.12 (m, 2H), 4.00-3.88 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([N:14]([CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])=[O:4].[CH3:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38]=[O:39])[CH:34]=[CH:35][CH:36]=1>>[CH3:21][N:14]([C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:3](=[O:4])[CH2:2][NH:1][C:38]([NH:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH3:30])[CH:32]=1)=[O:39])=[O:13])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C(=O)c1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CN)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2C(=O)N(C)c2ccccc2)c1
Yield: 57.4 %

Procedure:
Using a procedure similar to that described in Example 27, but starting with tert-butyl 2-{2-amino-N-[2-(N-methylanilino)carbonylphenyl]acetamido}acetate (2.5 g) and 3-methylphenyl isocyanate (0.83 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{N-[2-(N-methylanilino)carbonylphenyl]-2-[3-(3-methylphenyl)ureido]acetamido}acetate (1.9 g), m.p. 145° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[C:12]([F:24])[CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([N:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:32]([NH:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:33])=[C:15]3[C:10]([CH:11]=[C:12]([F:24])[CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: Fc1ccc2c(NC3CCCCC3)n(-c3ccc(Cl)cc3)nc2c1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)N(c1c2ccc(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-6-fluoro-2H-indazol-3-yl]-cyclohexyl-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in toluene for 5 days under reflux conditions to give the title compound as off-white solid. MS: m/e=469.4 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[CH2:23]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2cccnc2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccnc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 91.7 %

Procedure:
1.50 g (6.9 mmol) of ethyl 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in N,N-dimethylformamide (30 mL), and 1.43 g (10.4 mmol) of potassium carbonate and 1.36 g (7.9 mmol) of benzyl bromide were added thereto. The resulting mixture was stirred for one whole day and night at room temperature. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The organic phase was dried, filtered, and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=3:7 to 1:1), and thus 1.95 g (yield: 92%) of the title compound was obtained as colorless crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4ccccc4)CC3)n1-2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ccccc3)CC2)C1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-phenyl-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.065 g, 0.16 mmol) and triethylamine (0.046 ml, 0.33 mmol) in dichloromethane (5 ml) was added methanesulphonyl chloride (0.013 ml, 0.17 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.043 g, 60%) as white solid. MS m/e: 457 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[OH:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[CH:25]2.[H-].[Na+]>CN(C=O)C>[CH:25]1[C:26]2[C:21](=[C:20]([O:19][C:5]3[N:4]=[N:3][C:2]([O:19][C:20]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:21]=4[CH:22]=[CH:23][N:24]=[CH:25]5)=[C:7]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[CH:6]=3)[CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:23][N:24]=1
Reactant: Oc1cccc2cnccc12
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4cnccc34)nnc2Oc2cccc3cnccc23)cc1
Temperature: 140 °C

Procedure:
To a solution of 3,6-dichloro-4-(4-trifluoromethyl-phenyl)pyridazine, (Example 45(d)), (100 mg, 0.3 mmol) and 5-hydroxyisoquinoline (112 mg, 0.7 mmol, Aldrich) in DMF (2.5 mL) was added NaH (32 mg, 0.8 mmol, 60% suspension in mineral oil, Aldrich) and the reaction mixture was heated at 140° C. for 10 min in a microwave synthesizer. The reaction mixture was allowed to cool to room temperature and partitioned between H2O/CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were concentrated in vacuum. The residue was evaporated onto SiO2 and purified by flash silica gel chromatography with 2M NH3 in MeOH/CH2Cl2 (0:1→1:49) as eluant to give the title compound as an white amorphous solid. Mp: 197–199° C. MS (ESI, pos ion.) m/z: 511 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:7])[CH2:3][OH:4].[N:16]#[C:17]Br>>[Cl:15][C:10]1[CH:9]=[C:8]([CH:6]([CH3:7])[CH2:5][C@H:2]2[CH2:3][O:4][C:17]([NH2:16])=[N:1]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: N#CBr
Reactant: CC(C[C@H](N)CO)c1ccc(Cl)c(Cl)c1
Product: CC(C[C@H]1COC(N)=N1)c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to example 1b (S)-2-amino-4-(3,4-dichloro-phenyl)-pentan-1-ol was reacted with cyanogen bromide to give (5)-4-[2-(3,4-dichloro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine (mainly one epimer). Colourless oil. MS (ISP): 277.1 ([{37Cl}M+H]+), 275.0 ([{37Cl35Cl}M+H]+), 273.1 ([{35Cl}M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[C:21]([O:29][CH3:30])=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[C:21]=3[O:29][CH3:30])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1c(F)cccc1B(O)O
Product: CCCNC(=O)c1nnc2c(-c3cccc(F)c3OC)cccc2c1N
Yield: 88 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (116 mg, 0.375 mmol) and (3-fluoro-2-methoxyphenyl)boronic acid (127 mg, 0.75 mmol) were reacted to afford the title compound (117 mg, 88% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.06 (t, J=6.0 Hz, 1H), 8.45 (dd, J=7.5, 2.2 Hz, 1H), 7.74-7.81 (m, 2H), 7.28-7.37 (m, 1H), 7.12-7.21 (m, 2H), 3.54 (s, 3H), 3.31 (apparent q, J=7.0 Hz, 2H), 1.56 (apparent sextet, J=7.0 Hz, 2H), 0.90 (t, J=7.0 Hz, 3H). MS APCI, m/z=355 (M+H) HPLC 1.86 min.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[BH4-].[Na+].S(=O)(=O)(O)O>C(O)C>[OH:12][C@@H:11]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCCC[C@H]1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 11.6 %

Procedure:
Ethyl cyclohexanone-2-carboxylate (85.0 g, 0.5 mole) was dissolved in ethanol (200 ml) and the solution cooled to 0° C. Sodium borohydride (13.2 g, 0.35 mole) suspended in ethanol (80 ml) was added in small portions whilst the temperature was maintained at below 0° C. After stirring for 2 hours at 0° C. the reaction mixture was made faintly acid by the addition of 50% sulphuric acid and filtered. The filtrate was concentrated in vacuo, taken up in ether and washed with sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated in vacuo. The residue was chromatographed on silica-gel, eluting initially with 3:1 hexane/ethyl acetate followed by 2:1 hexane/ethyl acetate to give 21.5 g of cis- and 10.0 g of trans-ethyl 2-hydroxycyclohexanecarboxylate.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[CH:45]1([C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:49])[CH2:47][CH2:46]1.P([O-])([O-])([O-])=O.[OH-].[Na+]>C(OCC)C.CCCCCC.CC(O)C>[C:50]1([CH:48]([CH:45]2[CH2:46][CH2:47]2)[OH:49])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C(c1ccccc1)C1CC1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CCCCCC
Product: OC(c1ccccc1)C1CC1
Temperature: 25 °C

Procedure:
A reaction mixture was formed by admixing (i) 50 mg NAD, (ii) 4 ml of 2-propanol and (iii) 5 mmoles of phenyl cyclopropyl ketone, Compound 7, in a liquid medium containing 1 gm of lyophilized PED alcohol dehydrogenase preparation, 75 ml of 50 mM phosphate buffer, pH 7.1, and 25 ml of hexane. The pH value of the reaction was maintained constant by addition of 1N NaOH. The reaction mixture was maintained at room temperature until product formation stopped. When product formation stopped, phenylcyclopropyl methanol, Compound 7a, was isolated by removal of the hexane layer and extraction of the aqueous layer with ethyl ether (3×75 ml).