Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[FH:25].[F-].[K+]>C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[F:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](F)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
10.0 g (24.3 mmol) of 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide were heated under reflux in 100 ml of anhydrous acetonitrile with 10.0 g (128 mmol) of potassium hydrogen difluoride for 6 hours. The mixture was then filtered, the solvent was stripped off in vacuo and the residue was taken up in methylene chloride. After filtration over a short silica gel column and concentration of the solution, it was possible to crystallize the product from ether. Yield 6.1 g (72%), melting point 100° C., [α·D20 =+17.5 (c=1.03 in CHCl3) [F. Micheel et al., Chem. Ber. 88, 475 (1955), melting point 98°-99° C., [α]D18 =+22 (CH3OH)]. 1H NMR (CDCl3): δ=5.26 (dd, 1-H), J1.2 =7.0, J1,F =50.0 Hz.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[F:42][C:43]1[C:48](O)=[C:47]([F:50])[C:46]([F:51])=[C:45]([F:52])[C:44]=1[F:53]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH:10]=[C:11]([C:13]([O:15][C:48]2[C:47]([F:50])=[C:46]([F:51])[C:45]([F:52])=[C:44]([F:53])[C:43]=2[F:42])=[O:14])[N:12]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Step 1, 2-(2-Chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic acid (1.5 g, 4.5 mmol) was dissolved in dichloromethane (40 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 946 mg, 4.95 mmol) and triethylamine (500 mg, 4.95 mmol) were added followed by pentafluorophenol (815 mg, 4.37 mmol). The mixture was stirred at rt under argon for one hour before it was washed with 5% HCl, sodium bicarbonate solution, and then brine. The organic layer was dried (MgSO4), filtered, and concentrated to give the crude product (1.26 g) which was chromatographed over silica gel (20% EtOAc in hexanes) to afford pentafluorophenyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate (0.73 g, 32% yield): LC-MS m/z 499.0 (MH+), retention time 3.93 min (method 1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:20]([OH:23])[CH2:21]Cl)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:20]2[CH2:21][O:23]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2c([C@H](O)CCl)ccc(OCc3ccccc3)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1ccc2c([C@H]3CO3)ccc(OCc3ccccc3)c2[nH]1
Reaction time: 18 h

Procedure:
8-Benzyloxy-5-((S)-2-chloro-1-hydroxy-ethyl)-1H-quinolin-2-one (0.55 g) is dissolved in acetone (20 mL). K2CO3 (0.58 g) is added and the reaction mixture is refluxed. The reaction is shown to be complete by TLC after 18 hours. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo. The product is triturated with diethyl ether, filtered and dried. TLC (silica, dichloromethane/methanol 25:1 Rf=0.45).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([CH2:36]I)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=3)=[CH:6][CH:7]=2)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)nc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cn3)cc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 6-(4-hydroxy-phenyl)-nicotinonitrile (Preparation 18) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (112 mg, 64.6%)
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:17])[CH:7]=1.[Cl:22][C:23]1[C:28]([CH2:29]Cl)=[C:27]([Cl:31])[CH:26]=[CH:25][C:24]=1[N:32]([CH3:51])[C:33](=[O:50])[CH2:34][NH:35][C:36](=[O:49])[CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]([NH:47][CH3:48])=[O:46])=[N:43][CH:44]=1>>[Cl:22][C:23]1[C:28]([CH2:29][O:16][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:10]=2[N:9]=[C:8]([CH3:17])[CH:7]=[C:6]3[O:5][CH2:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=2[F:1])=[C:27]([Cl:31])[CH:26]=[CH:25][C:24]=1[N:32]([CH3:51])[C:33](=[O:50])[CH2:34][NH:35][C:36](=[O:49])[CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]([NH:47][CH3:48])=[O:46])=[N:43][CH:44]=1
Reactant: CNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(CCl)c2Cl)cn1
Reactant: Cc1cc(OCc2ccccc2F)c2cccc(O)c2n1
Product: CNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(OCc5ccccc5F)cc(C)nc34)c2Cl)cn1
Yield: 53 %

Procedure:
4-((2-fluorobenzyl)oxy)-2-methylquinolin-8-ol from step 1 was reacted with 5-(3-((2-((2,4-dichloro-3-(chloromethyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylpicolinamide as described previously to give 5-(3-((2-((2,4-dichloro-3-(((4-((2-fluorobenzyl)oxy)-2-methylquinolin-8-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylpicolinamide in 53% yield. MS (+APCI) 718 (M+). 1H-NMR (CDCl3, δ ppm): 8.36 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.95 (bd, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.63 (m, 1H), 7.58 (m, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.25 (m, 4H), 7.15 (m, 1H), 7.05 (m, 1H), 6.77 (bs, 1H), 6.40 (bt, 1H), 5.62 (s, 2H), 5.38 (s, 2H), 3.76 (dd, J=5.2, 17.6 Hz, 1H), 3.46 (dd, J=3.6, 18 Hz, 1H), 3.22 (s, 3H), 3.00 (m, 6H), 2.69 (m, 2H), 2.56 (t, 2).
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1.N12CCN(CC1)CC2>C1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([N:14]2[C:15](=[O:16])[C:6]3([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]3)[NH:7][C:8]32[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:26])=[CH:20][CH:19]=1
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: O=C(Nc1ccc(Cl)cc1)N1C(=O)C2(CCCCC2)NC12CCCCC2

Procedure:
5.5 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 3.84 parts of p-chlorophenyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 100 parts of dry benzene were heated at reflux for 36 hours. The solvent was removed in vacuo to yield a solid material which was recrystallised twice from petroleum ether of boiling range 60° to 80°C affording 5.6 parts of 14-p-chlorophenylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one as colourless needles of melting point 139° to 141°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][O:44][CH2:45][CH2:46]O.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:46][CH2:45][O:44][CH3:43])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Yield: 80.9 %

Procedure:
In a manner similar to the method described in Example 7, chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (100.4 mg, 0.163 mmol) was reacted with N,N′-carbonyldiimidazole (Aldrich, 69.2 mg, 0.414 mmol) and then, a mixture of 2-methoxyethanol (Sigma Aldrich, 38.6 mg, 0.506 mmol) and sodium hydride (9.7 mg, 0.384 mmol) in tetrahydrofuran to give chiral 2-methoxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (89 mg, 81% yield). MS (ES+) m/z calcd. for C34H37Cl2F2N4O4 [(M+H)+]: 674. found: 674.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([O:19]C)=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([OH:19])=[O:18])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 65 °C
Yield: 9.3 %

Procedure:
To a solution of 74 (0.20 g; 5.32 mmol) in tetrahydrofuran (2.7 mL) were added aqueous sodium hydroxide (2.7 mL; 2N) and methanol (1.4 mL), sequentially. The reaction mixture was heated at 65° C. for 18 hours, allowed to cool to room temperature, and then extracted with aqueous sodium hydroxide (20 mL; 2N). The aqueous layer was washed with diethyl ether (30 mL×2), acidified with aqueous hydrochloric acid (20 mL; 6N), and extracted with dichloromethane (40 mL). The organic layer was successively washed with water (30 mL) and aqueous saturated sodium chloride (30 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield the title compound as a white solid (0.18 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]1(=[O:17])[O:16][CH2:15][CH2:14][O:13]1>>[CH3:9][O:8][Si:5]([O:10][CH3:11])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][NH:1][C:12](=[O:17])[O:13][CH2:14][CH2:15][OH:16]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: O=C1OCCO1
Product: CO[Si](CCCNC(=O)OCCO)(OC)OC
Reaction time: 24 h

Procedure:
3-Aminopropyltrimethoxysilane (20 g, 0.111 mol) was added to ethylene carbonate (9.82 g, 0.111 mol). The mixture homogenized while stirred and then became slightly warm. Stirring continued for 24 hours to give 2-hydroxylethyl N-(3-trimethoxysilylpropyl)carbamate. Distilled water (18 g) was added drop-wise under stirring to a mixture of 2-hydroxylethyl N-(3-trimethoxysilylpropyl)carbamate (15 g), methanol (5 g) and acetic acid (0.1 g) to form a hazy solution. Stirring continued for 12 hours resulting in clear water-miscible liquid (39.37 wt. % of hydroxyl-functional carbamoyl organosilicon compound(s)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH3:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:50]=1[NH2:51]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:51][C:50]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[CH3:44])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1ccccc1N
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4C)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 55 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with o-tolylamine yielded the title compound (55% yield) as a pale red foam. MS (ISP): m/z=680.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([O:25]CC)[N:14]([CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>CO.O1CCOCC1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([OH:25])[N:14]([CH2:15][CH2:16][NH2:17])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOc1nc2c(N)nc3cccnc3c2n1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCCn1c(O)nc2c(N)nc3cccnc3c21
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A solution of tert-butyl 2-(4-amino-2-ethoxy-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethylcarbamate (6 g, 16 mmol) in methanol (25 mL) was combined with a solution of hydrogen chloride in dioxane (102 mL of 4N). The reaction mixture was allowed to stir over night at ambient temperature and was then concentrated under reduced pressure to provide crude product as an orange solid. The solid was loaded onto a silica gel column. The column was eluted with 47.5% methanol/2.5% ammonium hydroxide in dichloromethane. The fractions were combined and concentrated under reduced pressure to provide an orange solid. The solid was triturated with hot acetonitrile and methanol and then allowed to cool. The solid was isolated by filtration and then washed sequentially with acetonitrile and diethyl ether to provide 3.5 g of 4-amino-1-(2-aminoethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-ol.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[NH:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2C(OC(C)(C)C)=O)=[O:5].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[OH:42][C:36]([C:38]([F:41])([F:40])[F:39])=[O:37].[C@H:7]12[CH2:12][C@H:10]([NH:9][CH2:8]1)[CH2:11][N:6]2[C:4]([C:3]1[CH:20]=[C:21]([CH:22]=[CH:23][C:2]=1[F:1])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](=[O:35])[NH:27][N:26]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the solution of (1S,4S)-tert-butyl 5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (1.23 g crude obtained from previous step) in DCM (50 ml) was added TFA (4 ml), and stirred for 16 h at room temperature. The reaction mixture was concentrated under vacuo to yield the crude product as yellow oil (2.64 g), used in next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[S:17][C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[S:17][C:16]([S:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:20])=[O:19])=[CH:15][CH:14]=1
Reactant: NCCCCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Product: O=C(O)CCCCCCCNS(=O)(=O)c1ccc(Cl)s1

Procedure:
8-Aminocaprylic acid (1.0 g, 0.006 mole) was treated with 5-chloro-2-thiophene sulphonyl chloride (1.37 g, 0.0063 mole) according to the method described in Example 4 to give the title compound after recrystallisation from isopropanol/water (1.39 g, m.p. 108°-9° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[CH:10](O)=O>C=O>[CH3:10][N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=CO
Reactant: O=C(O)C1CCNCC1
Agent: C=O
Product: CN1CCC(C(=O)O)CC1
Yield: 18 %

Procedure:
A solution of 4-piperidine carboxylic acid (1.0 g, 7.75 mmol) in a mixture of 90% formic acid (3 mL) and 37% formaldehyde solution (2 mL) was heated at reflux for 20 h. The volatiles were removed in vacuo and conc. HCl added to the residue. The reaction mixture was extracted with dichloromethane and washed with brine solution. The organic layer was dried over sodium sulfate, filtered and dried to afford 1-methyl-piperidine-4-carboxylic acid (0.20 g, 18%).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)=[O:13])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>C(O)CCC>[CH:19]1([NH:24][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12]([C:14]4[O:15][CH:16]=[CH:17][CH:18]=4)=[O:13])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1ccco1
Reactant: NC1CCCC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2cccc(NC3CCCC3)n2n1)c1ccco1
Reaction time: 0.33 h
Yield: 45.6 %

Procedure:
A sealed vessel containing furan-2-carboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (61 mg, 0.20 mmol, 1 mol eq.), cyclopentylamine (26 mg, 0.30 mmol, 1.5 mol eq.), di-iso-propylethylamine (60 pt, 0.32 mmol, 1.6 mol eq.) and n-butanol (0.75 ml) was irradiated at 220° C., with stirring, for 20 minutes. The solvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (28.4 mg, 46%). HPLC, Rt: 2.32 min (purity: 97%). LC/MS M+(ESI): 312.3.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClC1C=CC=CC=1>[C:4]1([CH:3]=[CH:2][CH:1]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=Cc1ccccc1
Reactant: ClCC=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Clc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: C(C=Cc1ccccc1)=Cc1ccccc1
Yield: 27.7 %

Procedure:
The procedure described in Example 1 is followed, except that 16.7 g (0.1 mol) of cinnamyl chloride, 13.0 g (0.125 mol) of styrene, 23.3 g (0.125 mol) of tri-n-butylamine, 100 ml of chlorobenzene and 0.225 g (0.001 mol) of palladium acetate are used. After a reaction time of 5 hours at a bath temperature of 140° C., 5.7 g (0.0277 mol) of 1,4-diphenyl-1,3-butadiene, corresponding to a yield of 27.7% of theory, are obtained; melting point 150°-152° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([Br:21])[CH:7]=1)=[O:5])C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27][NH2:28]>C(O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27][NH:28][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([Br:21])[CH:7]=1)=[O:5]
Reactant: COc1ccc(CN)cc1OC
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)NCc3ccc(OC)c(OC)c3)n2n1

Procedure:
7-Bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester, which may be prepared as in Example 6, (253 mg, 0.714 mmol) and 3,4-dimethoxybenzylamine (0.55 mL) were taken up in ethanol (4.0 mL). After 24 h the precipitate was removed by filtration and washed with ethanol to afford 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid 3,4-dimethoxy-benzylamide MS (APCI+): m/z 478.4 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[N:15]=[CH:14][N:13]=1.N1C=CC=CC=1>O>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[N:15]=[CH:14][N:13]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
75 μl of methanesulfonyl chloride was added to a mixture comprising 100 mg of 4-(3-amino-4-chlorobenzyl)amino-6-chloroquinazoline and 3 ml of pyridine. The obtained mixture was stirred at room temperature for 1.5 hours. 20 ml of water was added in portions to the reaction mixture to precipitate crystals. The crystals were recovered by filtration, washed with water and dried to give 109 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH:22]([CH3:24])[CH3:23])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>CO>[CH3:24][CH:22]([C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:18])[C:16]=2[CH:15]=1)[CH3:23]
Reactant: CCOC(=O)c1cc(C(C)C)sc1N
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: CO
Product: CC(C)c1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Yield: 20.1 %

Procedure:
A mixture of 24.0 g (0.1538 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 32.8 g (0.1538 mol) of 2-amino-5-(1-methylethyl)-3-thiophenecarboxylic acid, ethyl ester (Tetrahedron, Vol. 33, pages 2089-2092, 1977) is heated in a wax bath at 178°-182° C. for two hundred five minutes and then at 180°-196° C. for sixty-five minutes under nitrogen. The mixture is cooled, suspended in hot methanol and filtered to give 8.9 g of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 280°-282° C. after recrystallization from dimethylformamide.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.ClCCl>O1CCCC1.[Cl-].[Na+].O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:27]([C:26]3[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=3)=[NH:28])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(F)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: N=C(Nc1ccc2c(c1)OCCO2)c1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 2.39 g (15.8 mmol) of 1,4-benzodioxan-6-amine in 30 mL of tetrahydrofuran at ambient temperature was added 8.7 mL (17.4 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide and the resulting solution was stirred for 20 min. To this reaction mixture was added 1.91 g (15.8 mmol) of 4-fluorobenzonitrile all at once. The resulting mixture was stirred at ambient temperature overnight and then poured into brine (50 mL) and dichloromethane (150 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate; filtered and concentrated in vacuo to yield the title compound as yellow solid which was used without further purification. LC/MS 273.2 (M+1).