Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:30]([NH:32][C:33]([CH3:44])([CH3:43])[CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[O:31])=[CH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[F:45][C:46]1[CH:54]=[C:53]2[C:49]([C:50]([Sn](CCCC)(CCCC)CCCC)=[N:51][NH:52]2)=[CH:48][CH:47]=1>CN(C=O)C.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.[Cu]I>[Si:36]([O:35][CH2:34][C:33]([NH:32][C:30]([C:8]1[C:6]2=[N:7][C:2]([C:50]3[C:49]4[C:53](=[CH:54][C:46]([F:45])=[CH:47][CH:48]=4)[NH:52][N:51]=3)=[CH:3][N:4]=[C:5]2[N:10]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1)=[O:31])([CH3:43])[CH3:44])([C:39]([CH3:41])([CH3:40])[CH3:42])([CH3:38])[CH3:37]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Temperature: 85 °C
Reaction time: 4 h
Yield: 20.5 %

Procedure:
2-Bromo-N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (287 mg, 0.674 mmol) and 6-fluoro-3-(tributylstannyl)-1H-indazole (450 mg, 0.674 mmol) were dissolved in DMF (8 mL) under nitrogen. Pd(PPh3)4 (39 mg, 0.034 mmol) and CuI (26 mg, 0.136 mmol) were added and the mixture was sonicated for 5 min while bubbling nitrogen through it. The reaction mixture was then stirred at 85° C. for 4 h. The mixture was cooled, concentrated in vacuo and then purified by chromatography (silica, petroleum ether:EtOAC 5:1 v/v) to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 20%) as a white solid. 1H NMR (300 MHz, CD3C1): δ 8.55 (s, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 8.32 (s, 1H), 7.49-7.47 (m, 3H), 7.29-7.01 (m, 15H), 3.87 (s, 2H), 1.55 (s, 6H), 0.78 (s, 9H), 0.02 (s, 6H). LC-MS: 725.3 [M+H]+.
Reaction SMILES: O[C:2]([C:15]1[C:16](=[O:52])[NH:17][C:18](=[O:51])[N:19]([CH:50]=1)[C@@H:20]1[O:49][C@H:39]([CH2:40][O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:30]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@H:21]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:3]1([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]2[C:16](=[O:52])[NH:17][C:18](=[O:51])[N:19]([CH:50]=2)[C@@H:20]2[O:49][C@H:39]([CH2:40][O:41][Si:42]([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:44])[CH3:43])[C@@H:30]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:34])[CH3:33])[C@H:21]2[O:22][Si:23]([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(O)(c3ccccc3)c3ccccc3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(c3ccccc3)c3ccccc3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
The product of Example 1 step (i), (5-(hydroxy-(1,1-diphenyl)methyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine) (6.8 g), was dissolved in dichloromethane (80 ml) and triethylsilane (1.83 ml) and treated with trifluoroacetic acid (1.38 ml). After stirring for 20 minutes the solvents were removed under reduced pressure and any remaining traces removed by azeotroping three times with toluene. The remaining residue was dissolved in dimethylformamide (5 ml) and treated with imidazole (0.54 g) and t-butyldimethylsilylchloride (0.6 g). After stirring for 16 hours the mixture was partitioned between water and iso-hexane and the organic phase was washed with water, collected and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was purified by flash silica-gel chromatography eluting with ethyl acetate/iso-hexane mixtures to afford 5-diphenylmethyl-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine as a colourless foam (5.94 g).
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=2)=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:35]([C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[C:40]([OH:47])[CH:39]=1)(=[O:37])=[O:36]>>[C:1]([C:9]1[O:10][C:11]2[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][S:35]([C:38]3[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[C:40]([OH:47])[CH:39]=3)(=[O:37])=[O:36])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=2)=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: O=C(c1ccccc1)c1oc2ccccc2c1-c1ccc(-c2ccc(O)c([N+](=O)[O-])c2)cc1
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(C(=O)c5ccccc5)oc5ccccc45)cc3)cc2[N+](=O)[O-])cc1O

Procedure:
The title compound was prepared from 4′-(2-benzoyl-benzofuran-3-yl)-3-nitro-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a yellow solid, mp 105-107° C.; MS m/e 683 (M−H)+;
Reaction SMILES: [CH2:1]([P:3]([O-:8])[O:4][CH2:5][CH2:6][OH:7])[CH3:2].[CH3:9][C:10](=[CH2:13])[CH:11]=[O:12].[O-]CC.[Na+]>>[CH2:1]([P:3]([CH2:9][CH:10]([CH3:13])[CH:11]=[O:12])(=[O:8])[O:4][CH2:5][CH2:6][OH:7])[CH3:2]
Reactant: CCP([O-])OCCO
Reactant: C=C(C)C=O
Agent: CC[O-]
Agent: [Na+]
Product: CCP(=O)(CC(C)C=O)OCCO
Yield: 87.7 %

Procedure:
A 500 ml five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel is initially charged with 63.5 g (0.46 mol) of 2-hydroxyethyl ethylphosponite (produced as in Example 4) and 32.2 g (0.46 mol) of 2-methyl-2-propenal. While stirring, 25 ml of sodium ethoxide (30% in ethanol) are added dropwise at such a rate that a reaction temperature of 60° C. becomes established. A slightly yellow-colored liquid is obtained. The crude product thus obtained is distilled in vacuo to obtain 84 g (88% of theory) of 2-hydroxyethyl ethyl(2-methyl-2-formylethyl)phosphinate as colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8](=[O:19])[NH:9][C:10](=[O:18])[N:11]([CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:12]=1.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C@:28]23[CH2:33][C@H:32]2[CH2:31][NH:30][CH2:29]3)=[CH:24][CH:23]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+].[Cl:56]C(Cl)C>>[ClH:56].[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8](=[O:19])[NH:9][C:10](=[O:18])[N:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:30]2[CH2:31][C@H:32]3[C@:28]([C:25]4[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:27][CH:26]=4)([CH2:33]3)[CH2:29]2)[CH:12]=1
Reactant: CC(Cl)Cl
Reactant: Cc1ccsc1-c1cn(CCCC=O)c(=O)[nH]c1=O
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccsc1-c1cn(CCCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)[nH]c1=O
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 4-[5-(3-methyl-thiophen-2-yl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-butyraldehyde (Prep32, 30 mg, 0.11 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 21 mg, 0.09 mmol), AcOH (6 μl, 0.1 mmol) in dichloroethane (1.5 mL) and NaBH(AcO)3 (24 mg, 0.11 mmol) were added at 0° C. The reaction was stirred for 30 minutes at room temperature then 2N NaOH (1 mL) was added and the product extracted with ethyl acetate. The organic phase washed with brine, dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with DCM-MeOH—NH4OH (95-5-0.5) to give the title compound (26 mg, 48% yield) as a free base.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:32])[N:17]([C:21]2[CH:22]=[C:23]([CH:27]=[C:28]([F:31])[C:29]=2[CH3:30])[C:24]([OH:26])=O)[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].F[B-](F)(F)F.[N:38]1([O:47][C:48](N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CON>CN(C=O)C.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:32])[N:17]([C:21]2[CH:22]=[C:23]([CH:27]=[C:28]([F:31])[C:29]=2[CH3:30])[C:24]([NH:38][O:47][CH3:48])=[O:26])[CH:18]=[CH:19][N:20]=1)([CH3:12])[CH3:13]
Reactant: Cc1c(F)cc(C(=O)O)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CON
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CONC(=O)c1cc(F)c(C)c(-n2ccnc(NC(C)(C)c3ccccc3OCCCl)c2=O)c1
Reaction time: 0.25 h
Yield: 94.1 %

Procedure:
To 3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoic acid (Example 316c, 0.13 g) in DMF (3 mL) was added O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (0.182 g) and N,N-diisopropylethylamine (0.148 mL). The reaction was stirred for 15 min, then O-methylhydroxylamine hydrochloride (0.047 g) was added. The reaction mixture was stirred at room temperature overnight, then diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated to afford the subtitle compound (0.13 g).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[CH2:37][CH2:36][N:35]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH:8]=2)[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: Cc1ccc(-c2cc(CN3CCN(Cc4ccccc4)CC3)c(=O)n(CC(C)C)n2)cc1
Yield: 97.7 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and 1-benzylpiperazine were reacted to yield the title compound as a pale yellow oil (yield: 97.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: Brc1ccccn1
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ccccn1
Yield: 34.8 %

Procedure:
The title compound was prepared from sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (250 mg, 0.81 mmol) and 2-bromopyridine (76 μL, 0.79 mmol) according to the method of Example 6 Step 4. Purification by flash column chromatography eluting with a 20-40% ethyl acetate/isohexane gradient gave 2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}pyridine (0.10 g, 34%). 1H NMR (400 MHz, CDCl3) δ 8.70 (1H, s), 8.68-8.65 (1H, m), 8.33-8.22 (1H, m), 8.07 (1H, d, J=8.6 Hz), 8.04-7.92 (4H, m), 7.82 (1H, dd, J=1.8, 8.6 Hz), 7.69-7.65 (2H, m), 7.46-7.44 (1H, m), 7.22-7.16 (2H, m); m/z (ES+) 364 [MH+].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][N:13]=2)[CH2:8]1.[CH2:24]([Sn](CCCC)(CCCC)C=C)[CH2:25]CC>CN(C=O)C.C(N(CC)CC)C.Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:24]=[CH2:25])=[CH:14][N:13]=2)[CH2:8]1
Reactant: Clc1ccc(CN[C@H]2CCN(c3ccc(I)cn3)C2)c(Cl)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 65 °C

Procedure:
Dissolve (S)-(2,4-dichlorobenzyl)-[1-(5-iodopyridin-2-yl)-pyrrolidin-3-yl]-amine hydrochloride (200 mg, 0.41 mmol) in DMF (7 mL) and triethylamine (60 μL). Add tetrakis(triphenylphosphine)palladium (0) (24 mg, 0.021 mmol) and tributyl(vinyl)tin (150 μL, 0.49 mmol). Heat the mixture at 65° C. overnight. Cool to room temperature, dilute with 1 N HCl (15 mL). Wash the mixture with dichloromethane (3×). Basify the aqueous solution to about pH=9 by adding solid potassium carbonate. Extract with dichloromethane (3×), dry (magnesium sulfate), concentrate and chromatograph on silica gel, eluting with 10:90 to 1:1 ethyl acetate:hexanes, to give the title compound as a residue. Dissolve the residue in methanol, add 1 N HCl in methanol (1 mL). Concentrate and dry in a vacuum oven at 60° C. to give the title compound as its hydrochloride salt (97 mg, 56%): 1H NMR (400 MHz, MeOH-d4) 8.30 (dd, 1H, J=8.8, 2.0 Hz), 7.97 (d, 1H, J=2.4 Hz), 7.71 (d, 1H, J=8.0 Hz), 7.68 (d, 1H, J=1.6 Hz), 7.50 (dd, 1H, J=8.0, 2.2 Hz), 7.16 (d, 1H, J=9.2 Hz), 6.70 (dd, 1H, J=17.6, 11.2 Hz), 5.87 (d, 1H, J=17.6 Hz), 5.40 (d, 1H, J=11.2 Hz), 4.55-4.47 (m, 2H), 4.34-4.28 (m, 1H), 4.18-4.13 (m, 1H), 3.97-3.91 (m, 2H), 3.80-3.74 (m, 1H), 2.77-2.68 (m, 1H), 2.55-2.46 (m, 1H), MS (ES): m/z 348 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=1[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:15][CH2:16][CH:17]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(CC(=O)N2CCC(c3ccncc3)CC2)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(CC(=O)N3CCC(c4ccncc4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 33.7 %

Procedure:
With 290 mg of the compound obtained in Step 51-2 and, 202 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 150 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][N:16]3[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]3)[N:4]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(Cc2nc(-c3ccc(Cl)cc3)oc2C)CC1
Temperature: 25 °C
Yield: 91 %

Procedure:
The mixture of 4-(chloromethyl)-2-(4-chlorophenyl)-5-methyloxazole (1.21 g, 5 mmole, commercially from Fluorochem) and ethyl piperidine-4-carboxylate (0.81 mL, 1.05 equiv.), K2CO3 (1.03 g, 1.5 equiv) in dioxane was stirred at 70° C. for 2 h. The reaction solution was cooled to room temperature and the solid was filtered off, rinsed with dichloromethane. The filtrate was concentrated and the residue was recrystallized from hexane to furnish Ethyl 1-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methyl)piperidine-4-carboxylate (1.65 g, 91%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][CH2:16][CH:17]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[S:19][CH2:18]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Cl:27][CH2:28][C:29](Cl)=[O:30]>ClCCl>[C:8]([O:12][C:13]([NH:15][CH2:16][CH:17]1[N:22]([C:29](=[O:30])[CH2:28][Cl:27])[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[S:19][CH2:18]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCC1CSc2ccccc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CSc2ccccc2N1C(=O)CCl
Temperature: 0 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A 0.48 ml (3.47 mmol) portion of triethylamine was added to dichloromethane solution (10 ml) containing 0.81 g (2.89 mmol) of 3-(t-butoxycarbonyl)aminomethyl-3,4-dihydro-2H-1,4-benzthiazine and cooled to 0° C. This was mixed with 0.28 ml (3.47 mmol) of chloroacetyl chloride and stirred at room temperature for 3 hours. The reaction solution was poured into ice water and extracted with chloroform. The extract was washed with dilute hydrochloric acid and dried (Na2SO4), and then the solvent was removed by evaporation under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (180 cc; elution by ethyl acetate-hexane=1:1) and further recrystallized from ethyl acetate-hexane to obtain 0.64 g of the title compound (62% in yield).
Reaction SMILES: C(OC([N:8]1[C:12]2=[CH:13][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15](=[O:17])[CH:16]=[C:11]2[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[CH2:18]([N:14]1[C:15](=[O:17])[CH:16]=[C:11]2[CH2:10][CH2:9][NH:8][C:12]2=[CH:13]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(=O)n(Cc3ccccc3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: O=c1cc2c(cn1Cc1ccccc1)NCC2

Procedure:
A mixture of 6-benzyl-5-oxo-2,3,5,6-tetrahydro-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (0.050 g, 0.15 mmol), 1,4-dioxane (1 mL) and a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.5 mL) was stirred at 20° C. for 18 h, then was evaporated in vacuo. The residue was dissolved in MeOH then re-evaporated and the azeotrope process repeated to give the title compound as a pale green glass, used without further purification. MS: [M+H]+=227.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.[NH2:19][C@H:20]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH3:44])=[C:39]([CH2:45][CH3:46])[CH:38]=1)[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH2:25][CH2:24]1)=[O:22]>>[CH2:45]([C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][C:40]=1[CH2:43][CH3:44])[CH2:36][C@@H:20]([NH:19]/[C:4](=[N:7]/[C:8]#[N:9])/[N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:5][CH2:6]1)[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)[CH2:25][CH2:24]1)=[O:22])[CH3:46]
Reactant: CCc1ccc(C[C@@H](N)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1CC
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Product: CCc1ccc(C[C@@H](N/C(=N/C#N)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 73 from 3-piperidin-4-yl-1,3,4,5-tetrahydrobenzo[d][1,3]diazepin-2-one and (R)-2-amino-3-(3,4-diethyl-phenyl)-1-[4-(4-methylpiperazin-1-yl)-piperidin-1-yl]-propan-1-one
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([O:11]CC=C)=O)[CH:2]=[CH2:3].[C-]#[N:16].[Na+]>N.CO>[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([NH2:16])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@@H]1CCCN1CC=C
Reactant: [C-]#N
Agent: N
Agent: [Na+]
Solvent: CO
Product: C=CCN1CCC[C@H]1C(N)=O
Yield: 81 %

Procedure:
Allyl (S)-1-allyl-2-pyrrolidinecarboxylate (2.5 g, 12.8 mmol; and NaCN (64 mg, 1.3 mmol) in 50 ml 9M ammonia in methanol were stirred at 35° C. for 27 h. GLC showed a complete conversion. After evaporation the residue was dissolved in Et2O and washed with brine. Drying (Na2SO4), evaporation and recrystallization gave 1.6 g (81%) of the title amide identical with the one made in Example 8A.
Reaction SMILES: [CH2:1]([CH:11]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68]CCCCCC)[CH2:12][N:13]=[C:14]([C:16]1[C:25]2[C:24]([C:26]([OH:28])=[O:27])=[C:23]([Br:29])[C:22]([Br:30])=[C:21]([C:31]([OH:33])=[O:32])[C:20]=2[C:19]([C:34](=[N:36][CH2:37][CH:38]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]CCCC)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]CCCCCC)[OH:35])=[C:18]([Br:61])[C:17]=1[Br:62])[OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CCCC.C(C(CCCCCC)CN)CCCCC>>[CH2:51]([CH:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][N:36]=[C:34]([C:19]1[C:20]2[C:21]([C:31]([OH:33])=[O:32])=[C:22]([Br:30])[C:23]([Br:29])=[C:24]([C:26]([OH:28])=[O:27])[C:25]=2[C:16]([C:14](=[N:13][CH2:12][CH:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[OH:15])=[C:17]([Br:62])[C:18]=1[Br:61])[OH:35])[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)CN=C(O)c1c(Br)c(Br)c(C(O)=NCC(CCCCCCCCCC)CCCCCCCCCCCC)c2c(C(=O)O)c(Br)c(Br)c(C(=O)O)c12
Agent: CCCCCCC(CN)CCCCCC
Product: CCCCCCC(CCCCCC)CN=C(O)c1c(Br)c(Br)c(C(O)=NCC(CCCCCC)CCCCCC)c2c(C(=O)O)c(Br)c(Br)c(C(=O)O)c12
Yield: 22 %

Procedure:
The same synthetic method for compound 22 was used except using 2-hexyloctyl amine instead of 2-decyltetradecyl amine, and the yield was 22% (calculated based on TBNDA as a starting material).