Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[C:9]([CH3:17])[N:8]=1.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:11]([C:10]3[C:9]([CH3:17])=[N:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:16][CH:15]=3)=[O:13])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)nc1C
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3C)CC2)c(C)c1
Yield: 67.2 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylnicotinate (220 mg) described in Preparation Example 37 and 1-(3,5-dimethylpyridin-2-yl)piperazine (186 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (235 mg) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C1N=CN([C:10](N2C=NC=C2)=[O:11])C=1.CCN(C(C)C)C(C)C.[C:26]([O:30][C:31](=[O:52])[NH:32][CH2:33][CH2:34][C@H:35]([N:37]1[CH2:42][CH2:41][CH:40]([NH:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=2)[CH2:39][CH2:38]1)[CH3:36])([CH3:29])([CH3:28])[CH3:27]>CC#N>[C:26]([O:30][C:31](=[O:52])[NH:32][CH2:33][CH2:34][C@H:35]([N:37]1[CH2:38][CH2:39][CH:40]([N:43]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=2)[C:10]([NH:4][O:3][CH3:2])=[O:11])[CH2:41][CH2:42]1)[CH3:36])([CH3:27])([CH3:28])[CH3:29]
Reactant: C[C@H](CCNC(=O)OC(C)(C)C)N1CCC(NCc2cccc(Cl)c2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CON
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CONC(=O)N(Cc1cccc(Cl)c1)C1CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
To a solution of methoxyamine HCl (0.25 g, 3.04 mmol) in CH3CN (5 ml) was added CDI (0.49 g, 3.04 mmol) and DIPEA (0.53 mL, 3.04 mmol). The mixture was stirred at 60° C. for 2 h, then a solution of {(R)-3-[4-(3-chloro-benzylamino)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester (305 mg, 0.76 mmol) in CH3CN (5 ml) was added to the previous mixture. After stirring at 60° C. overnight, the mixture was concentrated in vacuo and diluted with CH2Cl2 (15 ml) and saturated NaHCO3 (20 ml). The aqueous layer was extracted with CH2Cl2 (3×10 ml), then the combined organic extracts were dried over Na2SO4 and concentrated. The crude product contained 2:1 product/starting material in the 1H NMR and was purified by flash chromatography (CH2Cl2, 7% MeOH, 1% NH4OH) to afford ((R)-3-{4-[1-(3-chloro-benzyl)-3-methoxy-ureido]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester as a yellow oil (215 mg, 60%). 1H NMR (CDCl3) δ 0.92-0.95 (d, 3H, J=9 Hz), 1.37 (s, 9H), 1.47-1.82 (m, 6H), 2.13-2.25 (m, 1H), 2.48-2.57 (m, 1H), 2.63-2.89 (m, 3H), 2.99-3.09 (m, 1H), 3.23-3.38 (m, 1H), 3.65 (s, 3H), 4.14-4.26 (m, 1H), 4.31 (s, 2H), 5.90 (br s, 1H), 6.97 (s, 1H), 7.06-7.17 (m, 1H), 7.22 (s, 1H), 7.29 (s, 1H), 7.69 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:12]=1[C:13]([NH2:15])=[O:14].C(N)CN.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:12]=1[C:13]([NH:15][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:14]
Reactant: Fc1c(I)ccnc1Cl
Reactant: NC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: NCCN
Product: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 30.5 %

Procedure:
A mixture of 2-chloro-3-fluoro-4-iodopyridine (4.78 g, 18.6 mmol), 2-chloro-6-nitrobenzamide (3.91 g, 19.5 mmol), ethane-1,2-diamine (0.2 mL, 2.97 mmol), copper(I) iodide (0.57 g, 2.97 mmol) and K3PO4 (7.90 g, 37.2 mmol) in dioxane (80 mL), was degassed with a stream of argon and the reaction mixture was then heated under reflux for 4 hours. After cooling to room temperature, the crude reaction mixture was filtered through Celite® washing with dioxane. The filtrate was concentrated to dryness under reduced pressure and the resultant residue was purified by column chromatography on silica gel eluting with 0-100% ethyl acetate in petroleum ether (40-60° C.), to afford the title compound as a pale yellow solid (1.87 g, 31% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.42-11.37 (br s, 1H), 8.35-8.24 (m, 3H), 8.08 (dd, J=1.1, 8.1 Hz, 1H), 7.81 (t, J=8.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:39])=[C:15]([C:19]2[N:20]=[C:21]([C:35]([CH3:38])([CH3:37])[CH3:36])[S:22][C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[N:25]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:10].CN(C([O:47]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:64][CH2:65][N:66](C(C)C)[CH:67]([CH3:69])C>CN(C)C=O>[CH3:38][C:35]([C:21]1[S:22][C:23]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][CH2:31][C:32]([N:66]3[CH2:67][CH2:69][O:47][CH2:64][CH2:65]3)=[O:33])[N:25]=2)=[C:19]([C:15]2[C:14]([F:39])=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])(=[O:11])=[O:10])[CH:18]=[CH:17][CH:16]=2)[N:20]=1)([CH3:37])[CH3:36]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(CCC(=O)O)n2)s1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(CCC(=O)N3CCOCC3)n2)s1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
3-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}propanoic acid (200 mg, 0.347 mmol) was taken up in N,N-dimethylformamide (DMF) (2 ml). HATU (0.158 g, 0.416), DIEA (0.134 g, 1.041 mmol), and morphiline (0.060 g, 0.694) were added. After 30 min, the reaction mixture was concentrated and residue was purified via Gilson Acidic HPLC (10 to 90% gradient, Acetonitrile/H2O+TFA; C18 column) to obtain the title compound (147 mg, 53%) as white solid. MS (ESI): 646 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:9]=3[N:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[Cl:33].Cl.Cl[CH2:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:33][C:3]1[CH:4]=[C:5]([O:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:20][CH:21]=4)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:9]=3[N:10]=[CH:11][N:12]=2)[CH:31]=[CH:32][C:2]=1[NH2:1]
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(O)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Reactant: CCN(CC)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1ccc(-c2cc3c(Oc4ccc(N)c(Cl)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
After dissolving 47 mg of the 4-[4-(4-amino-3-chlorophenoxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol synthesized in Production Example 160-1 in 0.5 ml of dimethylformamide, there were added 56 mg (3.1 equivalents) of (3-chloropropyl)diethylamine hydrochloride and 94 mg (7 equivalents) of potassium carbonate, and the mixture was stirred at 80° C. for 24 hours. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethylacetate) to obtain 49 mg of the title compound.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([CH2:28][CH3:29])[CH:20]=1>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Pb+3:17])=[C:21]([CH2:28][CH3:29])[CH:20]=1
Reactant: CCc1cc(Br)ccc1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Product: CCc1cc(Br)ccc1[Pb+3]
Temperature: 40 °C
Yield: 44.8 %

Procedure:
To a mixture of lead tetraacetate (53 g, 0.12 mol) and mercuric diacetate (2.5 g, 0.0078 mol), thoroughly flushed with nitrogen, is added anhydrous chloroform (250 ml). This mixture is warmed to 40° C. and 4-bromo-2-ethylphenylboronic acid (25 g, 0.11 mol) is added in one portion and the mixture is stirred and heated at this temperature for 4 hours. After cooling to room temperature, cooled in an ice bath, filtered through a plug of diatomaceous earth and the filtrate is concentrated to approximately a quarter of its volume. Hexane is added to induce crystallization and the solvents evaporated under reduced pressure. Trituration with hexane gives 4-bromo-2-ethylphenyl lead triacetate (28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH:23]([F:25])[F:24])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[NH2:21])[CH:7]=1.[N:26]1[N:30]2[CH:31]=[CH:32][CH:33]=[N:34][C:29]2=[C:28]([C:35](Cl)=[O:36])[CH:27]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH:23]([F:24])[F:25])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[N:11]=[CH:10][C:9]=2[NH:21][C:35]([C:28]2[CH:27]=[N:26][N:30]3[CH:31]=[CH:32][CH:33]=[N:34][C:29]=23)=[O:36])[CH:7]=1
Reactant: O=C(Cl)c1cnn2cccnc12
Reactant: C[Si](C)(C)CCOCn1ncc(N)c1-c1cc(Cl)ccc1OC(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ncc(NC(=O)c2cnn3cccnc23)c1-c1cc(Cl)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of 5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylamine (60.0 g, 154 mmol) in THF (100 mL) was added dropwise over 30 minutes to an ice/water cooled mixture of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (27.8 g, 153 mmol), and DIPEA (49.5 g, 383 mmol) in THF (300 mL). On complete addition the mixture was left to stir at room temperature for 1 hour. The solvent was evaporated and the residue diluted with 0.5 N aqueous HCl and extracted with ethyl acetate. The combined organic extract was passed through Celite® to remove the residual solid and the filtrate washed with 1M aqueous K2CO3, water and brine, dried (Na2SO4) and evaporated to give a red solid. The solid was triturated with 10% diethyl ether in cyclohexane. The solid was collected by filtration, washed with 1:1 diethyl ether in cyclohexane and left to air dry to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-4-yl]amide as an off-white solid (59.2 g, 73%). 1H NMR (300 MHz, CDCl3): δ (ppm) 9.61 (s, 1H), 8.77-8.78 (m, 1H), 8.51 (dd, 1H), 8.36 (s, 1H), 7.65 (d, 1H), 7.52 (dd, 1H), 7.36 (d, 1H), 7.29 (s, 1H), 7.01 (dd, 1H), 6.42 (t, 1H), 5.39-5.41 (m, 2H), 3.60-3.64 (m, 2H), 0.87-0.89 (m, 2H), 0.09 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:17])[C:10]([C:18]([OH:20])=O)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.O.[NH2:28][NH2:29]>ClCCl.C(OCC)C>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:17])[C:10]([C:18]([NH:28][NH2:29])=[O:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Reactant: NN
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: NNC(=O)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Reaction time: 2 h

Procedure:
To a suspension of 1-cyclohexylmethyl-7-chloro-1H-indole-3-carboxylic acid (as prepared in Example 16; (2.0 g, 6.8 mmol) in dichloromethane (60 ml) was added oxalyl chloride (1.2 ml, 14 mmol) and the reaction stirred for 2 h and left to stand overnight. The solvent and excess reagent was removed in vacuo. The resulting residue was dissolved in dichloromethane (10 ml) and added dropwise to a cooled solution (ice/methanol bath) of hydrazine hydrate (1.7 ml, 34 mmol) in diethyl ether (60 ml) over 5 mins. The reaction mixture was then stirred for a further 40 mins before being reduced to half its volume in vacuo and filtered. The filtrate was concentrated further and the resulting precipitate filtered. The precipitates were combined and dried in vacuo to afford 1-cyclohexylmethyl-7-chloro-1H-indole-3-carboxylic acid hydrazide (2.3 g, 7 mmol).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([C@@H:36]([CH3:39])CO)[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[NH2:43][C@H](C)CO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:3]([NH:43][CH2:39][CH2:36][N:34]([CH2:33][C:31]1[S:30][CH:29]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:14][CH2:15]2)[CH:32]=1)[CH3:35])(=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)[C@@H](C)CO)c4)cc23)CC1
Reactant: C[C@@H](N)CO
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CCNC(C)=O)c4)cc23)CC1
Yield: 30.8 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting N-(2-aminoethyl)acetamide (1.20 mmol) for (2R)-2-amino-1-propanol to afford 13.6 mg of the title compound (30.8%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N-:53][CH2:54][CH:55]([OH:62])[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH:55]([OH:62])[C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(C[N-]CC(O)c2ccccc2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccccc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
To a solution of 100 mg (0.62 mmol) of 1H-indole-7-carboxylic acid and 200 mg of TBTU (0.62 mmol) in 8 ml DMF, were added 0.53 ml (3.1 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 176 mg (0.62 mmol) of [rac]-(4-tert-butyl-benzyl)-(2-hydroxy-2-phenyl-ethyl)-amide were added. After stirring for 17 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:4) to give 181 mg white solid (66%). MS (ISP) 427.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH2:14])[CH:6]=1)=[O:4].[Cl:15][C:16]1[N:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1.ClCCl.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:22]([C:19]2[CH:20]=[N:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[O:23])[CH:6]=1)=[O:4]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: COC(=O)c1ccc(=O)n(CCN)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(=O)n(CCNC(=O)c2ccc(Cl)nc2)c1
Temperature: -8 °C
Reaction time: 0.5 h

Procedure:
To a 1 00 ml round bottomed flask fitted with a magnetic stirrer bar and nitrogen inlet was added the above amine (0.300 g, 1.53 mmol), 6-chloro-3-pyridinecarboxylic acid (0.241 g, 1.53 mmol), and dry dichloromethane 125.5 mmol). Upon cooling in a -8° C. ice bath with stirring, triethyl amine (1.07 ml, 7.65 mmol) and propylphosphonic acid anhydride (0.50 ml, added as a 0.50 ml ethyl acetate solution, Angew. Chemie 1980, 92(2), 129) were added. The flask was allowed to warm slowly to room temperature over 1.25 hours. Stirring was continued 30 minutes at which time the reaction mixture solution was washed with aqueous sodium bicarbonate (2X), brine, and dried (Na2SO4). Filtration, concentration and purification via medium pressure liquid chromotography (silica gel, 4% methanol/dichloromethane) have the desired product, MP: 188°-190° C.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH:31]=O>ClCCl>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH:31]=[CH:6][C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1OC
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Carbethoxymethylene triphenylphosphorane (150 g, 0.3 mol) was added to a solution of 3,4-dimethoxybenzaldehyde (50 g, 0.3 mol) in dry dichloromethane (150 ml), and the mixture was stirred at room temperature overnight. The solution was concentrated to about 50 ml, and the precipitate was filtered off and washed with hexane-dichloromethane (4:1, v/v). The combined filtrates were evaporated to a residue, which was purified by silica gel chromatography using hexane-ethyl acetate (9:1, v/v) as the eluant. The title compound was isolated as a crystalline mass (65 g, 91%), m.p. 52°-53° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19]([O:23][C:24]([NH:26][C:27]([CH3:45])([CH3:44])[CH2:28][C:29]([NH:31][C@@H:32]1[CH2:38][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[NH:34][C:33]1=[O:43])=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:16]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:34]2[C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[CH2:37][CH2:38][C@@H:32]([NH:31][C:29](=[O:30])[CH2:28][C:27]([NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])([CH3:45])[CH3:44])[C:33]2=[O:43])=[CH:4][CH:5]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Product: CC(=O)Oc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from 4-bromomethyl-2'-acetoxy-1,1'-biphenyl and 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step I) by the procedure described in Example 1, Step Q. 1H NMR (200 MHz, CDCl3): δ 1.38 (s, 6H), 1.45 (s, 9H), 1.85 (m, 1H), 2.02 (s, 3H), 2.35-2.65 (m, 5H), 4.52 (m, 1H), 4.84 (d, 15 Hz, 1H), 5.30 (d, 15 Hz, 1H), 6.71 (d, 7 Hz, 1H), 7.1-7.4 (m, 12H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=O)(C)(C)C.N1C=CC=CC=1.[C:24](Cl)(=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.C(Cl)(Cl)Cl>[C:24]([NH:14][C@H:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])(=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NCCCC[C@H](NC(=O)C=Cc1ccccc1)C(=O)O

Procedure:
Nε-t-Butoxycarbonyl-L-lysine (2.58 g) was dissolved in 50 ml of dimethylformamide, and 30 ml of anhydrous pyridine was added to the solution. To the mixture was added a solution of cinnamoyl chloride in chloroform (1.665 g/20 ml) was added, and the reaction was carried out at 40° C. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in 3.6N HCl/dioxane (33 ml) and, after 4 hours of standing, the solution was concentrated under reduced pressure to give the desired compound (2.43 g; hereinafter referred to as compound B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]3=[CH:11][NH:12][C:13](=[O:22])[C:14]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)=[C:8]3[NH:7][C:6]=2[CH:23]=1.[OH-:24].[Na+].[CH2:26]=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]3=[CH:11][N:12]([CH2:26][OH:24])[C:13](=[O:22])[C:14]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)=[C:8]3[NH:7][C:6]=2[CH:23]=1
Reactant: C=O
Reactant: [OH-]
Reactant: O=c1[nH]cc2c(c1-c1ccc(Cl)cc1)Nc1cc(Cl)ccc1S2
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccc(Cl)cc1N2
Yield: 87 %

Procedure:
To 5.0 g. of 7-chloro-4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]-benzothiazin-3(2H)-one (13.8 mmol.) in 50 ml. dimethylformamide was added 30 ml. of a 5% sodium hydroxide solution (37.5 mmol.) and the resulting suspension was heated on a steam bath until the solid dissolved. To the resulting solution was then added 50 ml. of 36% formaldehyde solution (60.0 mmol.), and the resulting reaction mixture was heated on a steam bath for 30 minutes, then cooled to room temmperature, yielding a yellow precipitate. The mixture was filtered, and the collected precipitate was washed with water and dried under vacuum at room temperature to yield 7-chloro-4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one as a yellow solid (4.7 g.; 87% yield) having the structural formula, ##STR13## a melting point of 295°-300° C. (with decomposition) and the following elemental analysis:
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH:4]3[CH:5]([CH2:6]2)[CH:3]13.[C:9](Cl)(Cl)=[S:10]>C(Cl)(Cl)Cl>[N:1]([CH:2]1[CH:7]2[CH2:8][CH:4]3[CH:5]([CH2:6]2)[CH:3]13)=[C:9]=[S:10]
Reactant: S=C(Cl)Cl
Reactant: NC1C2CC3C(C2)C13
Solvent: ClC(Cl)Cl
Product: S=C=NC1C2CC3C(C2)C31
Reaction time: 2 h

Procedure:
3-Aminotricyclo[2,2,1,02,6 ]heptane (21 g.) (prepared as described in U.K. Patent Specification No. 1,051,319), was dissolved in chloroform (25 ml.) and added slowly, below 10°, to a stirred solution of thiophosgene (22 g.) in chloroform (20 ml.). When addition was complete the mixture was allowed to attain ambient temperature and stirred a further 2 hours. The chloroform solution was consecutively washed with 20 ml. portions of water, 1N NaOH, and water again, dried over anhydrous MgSO4, filtered and the chloroform evaporated in vacuo. The residual oil was fractionally distilled in vacuo to give 3-isothiocyanatotricyclo[2,2,1,02,6 ]heptane, b.p. 70°-76° at 0.4 mm. Hg. pressure.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[C:5]#[N:6])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: C1COCCN1
Product: N#Cc1cc(N2CCOCC2)cc(C(F)(F)F)c1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 3-fluoro-5-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH) and morpholine (Fluka, Buchs, Switzerland), with a reaction temperature of 105° C. for 14 hours.