Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[CH2:16]3)[C:12]3[C:11]4[CH:31]=[CH:32][CH:33]=[CH:34][C:10]=4[S:9][C:8]=3[NH:7][C:6]=2[CH:35]=1.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClC(Cl)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:36])[C@@H:17]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[CH2:16]3)[C:12]3[C:11]4[CH:31]=[CH:32][CH:33]=[CH:34][C:10]=4[S:9][C:8]=3[NH:7][C:6]=2[CH:35]=1
Reactant: COc1cccc(CC[C@H]2CN(C3=Nc4ccc(F)cc4Nc4sc5ccccc5c43)CCN2)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1cccc(CC[C@H]2CN(C3=Nc4ccc(F)cc4Nc4sc5ccccc5c43)CCN2C)c1
Yield: 80.6 %

Procedure:
Using a method similar to the method of Example 543, using (S)-9-fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.164 g, 0.337 mmol), sodium triacetoxyborohydride (0.107 g, 0.505 mmol), and aqueous formaldehyde (0.038 mL, 0.50 mmol) in dichloroethane gives the title compound (0.136 g): mass spectrum (APCI+, m/e): 501 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]>CS(C)=O>[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([O:5][CH2:4][CH2:3][O:2][CH3:1])[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]
Reactant: COCCO
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCOc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxyethanol (0.118 mL, 1.50 mmoles) in DMSO (5 mL) was added sodium hydride (Aldrich, 60% dispersion, 0.0720 g, 1.80 mmoles), followed by stirring until H2 evolution ceased (15 minutes). One milliliter of this alkoxide stock solution was added to N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloropyrimidin-4-yl]benzamide (0.147 g, 0.249 mmoles, reference example 1az), followed by heating (60° C.). After two hours, another 0.5 mL of the alkoxide stock solution was added. After two more hours, the reaction was quenched with water (40 mL) and the resulting precipitate collected by filtration. The precipitate was washed with water and CH2Cl2 and dried under vacuum to give the product as a white solid. MS (ion spray) m/z 442 (M+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)=[O:34])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CCOCC1

Procedure:
The title compound, white solid (66 mg, 60%), MS (ISP) m/z=439.4 [(M+H)+], mp 175° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and tetrahydro-pyran-4-carboxylic acid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH3:36])=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[CH:17][C:16]2=[O:37])=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:37]=[C:16]1[CH:17]=[C:18]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH3:36])=[CH:30][N:29]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][N:15]1[C:12]1[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=1
Reactant: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(=O)(=O)NC(C)(C)C)cc4)c(=O)c3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(N)(=O)=O)cc4)c(=O)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.2 %

Procedure:
To a stirring solution of N-tert-butyl-4-(2-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-1(2H)-yl)benzenesulfonamide (23 mg, 0.044 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (0.4 mL, 5 mmol, Aldrich). The reaction was stirred at room temperature for 2 days and then concentrated in vacuo to a yellow oil. The oil was purified by flash chromatography (SiO2, 0 to 5% MeOH in CH2Cl2) to yield 11 mg of the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (s, 2 H), 8.03 (d, J=8.53 Hz, 2 H), 7.54 (d, J=8.28 Hz, 2 H), 7.23 (d, J=7.78 Hz, 1 H), 6.07 (dd, J=7.65, 2.63 Hz, 1 H), 6.03 (d, J=2.51 Hz, 1 H), 4.56-4.65 (m, 1 H), 4.16-4.25 (m, 2 H), 3.60-3.71 (m, 2 H), 2.42 (t, J=7.53 Hz, 2 H), 2.04-2.14 (m, 2 H), 1.80-1.90 (m, 2 H), 1.53-1.64 (m, 2 H), 0.95 (t, J=7.28 Hz, 3 H). MS (ESI) 470 (M+H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[N:18]1([CH:24]([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:29]1[CH:28]=[CH:27][C:26]([CH:24]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:25])=[CH:31][CH:30]=1
Reactant: CC(c1ccc(B(O)O)cc1)N1CCCCC1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)N2CCCCC2)cc1
Yield: 5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.48 mmol) was reacted with 4-[1-(piperidin-1-yl)ethyl]phenylboronic acid (170 mg, 0.73 mmol) to afford the desired product (10 mg, 5%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.74-7.66 (m, 2H), 7.62-7.53 (m, 2H), 7.49-7.34 (m, 3H), 5.94 (d, J=5.4 Hz, 1H), 4.61 (q, J=6.9 Hz, 1H), 3.86-3.78 (m, 1H), 3.76 (s, 1H), 3.47 (d, J=12.6 Hz, 1H), 3.10-2.98 (m, 1H), 2.96-2.82 (m, 1H), 2.11-1.91 (m, 2H), 1.89 (d, J=7.0 Hz, 2H), 1.85-1.70 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19]C)=[O:18])=[N:6][C:7]=1[C:8]([NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:9].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([OH:19])=[O:18])=[N:6][C:7]=1[C:8]([NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:9]
Reactant: COC(=O)c1cccc(-c2cnc(N)c(C(=O)NC3CC3)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncc(-c2cccc(C(=O)O)c2)nc1C(=O)NC1CC1
Temperature: 92.5 °C
Yield: 15 %

Procedure:
Methyl 3-{5-amino-6-[(cyclopropylamino)carbonyl]pyrazin-2-yl}benzoate (480 mg, 1.5 mmol) was suspended in a 20 mL of 1:1 MeOH-5% aqueous sodium hydroxide and heated at 90-95° C. for 4 hours. The homogeneous reaction mixture was cooled to room temperature, concentrated to half the initial volume, cooled in an ice-bath, and acidified to pH 4 with concentrated HCl. A white solid precipitated and was collected by filtration, washed with water and dried in vacuo to give the intermediate 3-{5-amino-6[(cyclopropylamino)carbonyl]pyrazin-2-yl}benzoic acid. The acid (40 mg, 0.13 mmol) was dissolved in DMF (1 mL) and 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (30 mg, 0.16 mmol), and 4-methylmorpholine (30 mg, 0.28 mol) were added sequentially. After one hour benzylamine (30 mg, 0.27 mmol) was added to the reaction mixture and stirring was continued at room temperature for 18 hours. It was then diluted with ethyl acetate (10 mL), washed with water, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate, filtered, and concentrated. The oily residue was purified by flash chromatography (silica gel, eluted with ethyl acetate-hexanes gradient from 15% to 80% yield) to give 3-amino-N-cyclopropyl-6-(3-{[(phenylmethyl)amino]carbonyl}phenyl) pyrazine-2-carboxamide (a tan color solid, 23 mg, 44% yield): 1H NMR (400 MHz, DMSO-d6): 9.14 (t, 1H), 8.88 (s, 1H), 8.69-8.68 (d, 1H), 8.51 (s, 1H), 8.34-8.32 (d, 1H), 7.87-7.85 (d, 1H), 7.63-7.59 (b, 1H), 7.57-7.53 (t, 1H), 7.34-7.23 (m, 4H), 4.53-4.52 (d, 2H), 2.84-2.82 (m, 1H), 0.75-0.70 (m, 4H); MS (EI) for C22H21N5O2388 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[N:11][N:12]([C:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:4]=2[CH:3]=1
Reactant: O=Cc1nc(Cl)cc2c1c(N1CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCc1nc(Cl)cc2c1c(N1CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-Chloro-3-morpholino-1-trityl-1H-pyrazolo [4,3-c]pyridine-4-carbaldehyde (292.2 mg, 0.574 mmol) was dissolved in DCM (3 mL) and methanol (3 mL). Sodium borohydride (21.72 mg, 0.574 mmol) was then added and the reaction mixture was stirred at rt for 15 min. The reaction was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo while loading onto silica gel. Purification by flash chromatography (5-40% EtOAc/Hexanes) gave (6-chloro-3-morpholino-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol. MS ESI calc'd. For C30H28ClN4O2 [M+H]+ 511. found 511.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[N:3]1.[I:16]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[I:16][C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=1)[NH:5][CH:4]=[N:3][C:2]2=[O:1]
Reactant: COC(=O)c1cccc2c(=O)nc[nH]c12
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc(I)cc2c(=O)nc[nH]c12
Temperature: 40 °C
Reaction time: 192 h
Yield: 56 %

Procedure:
To a solution of Methyl 4-oxo-1,4-dihydroquinazoline-8-carboxylate (6.0 g, 0.0294 mol) in sulphuric acid (48 mL) was added N-Iodosuccinimide (53 g, 0.2382 mol; 4 equiv of NIS was added at the beginning of reaction and the remaining NIS was added at day-2, day-3 and day-4 of the reaction in equal portions). The reaction mixture was stirred at 40° C. for 8 days and cooled to room temperature. (The completion of reaction was monitored by LCMS). The reaction mixture was carefully poured on-to ice cold solution of saturated potassium carbonate and maintained a basic pH. The precipitate was filtered, washed with water and dried. This solid was further suspended in saturated sodium bicarbonate (100 mL) containing methanol (20 mL). After stirring for 30 min, the insoluble solid was collected by filtration. This material was further slurred in a mixture of chloroform and methanol (1:1) and filtered and dried under vacuum to afford (5.5 g, 56%) of the title compound as an off white solid. TLC—: Chloroform/Methanol: (9/1): Rf=0.25. LCMS: Mass found (M+1, 331.0).
Reaction SMILES: [CH:1]1([O:7][C:8]([O:10][CH2:11][CH2:12][O:13][C:14]([C:16]2[N:17]=[C:18]([C:47]([F:50])([F:49])[F:48])[N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:46])[CH2:26][C@H:27]([NH:38]C(OC(C)(C)C)=O)[CH2:28][C:29]4[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=4[F:37])[CH2:21][C:20]=23)=[O:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:51]>C(OCC)(=O)C>[ClH:51].[CH:1]1([O:7][C:8]([O:10][CH2:11][CH2:12][O:13][C:14]([C:16]2[N:17]=[C:18]([C:47]([F:48])([F:49])[F:50])[N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:46])[CH2:26][C@H:27]([NH2:38])[CH2:28][C:29]4[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=4[F:37])[CH2:21][C:20]=23)=[O:15])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)OCCOC(=O)OC3CCCCC3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)OCCOC(=O)OC3CCCCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 96.1 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (1-cyclohexyloxycarbonyloxy)-ethyl ester 38a (0.25 g, 0.347 mmol) and 5 mL of ethyl acetate were added into the reaction flask. A solution of 6.5 N hydrochloric acid in 3 mL of ethyl acetate was added to the flask under stirring. The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (1-cyclohexyloxycarbonyloxy)-ethyl ester hydrochloride 38 (0.22 g, yield 96.1%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][S:39][CH2:40][CH2:41][CH2:42][NH2:43]>>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][CH2:42][CH2:41][CH2:40][S:39][CH3:38])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Reactant: CSCCCN
Product: CSCCCNc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (150 mg, 0.264 mmol) and 3-(methylthio)-1-propanamine (300 mg, 2.85 mmol), the title compound was obtained as a crude yellow foam and used directly in the next step. MS (ESI): 637.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[C:4]1[C:18](Cl)=[O:19])[CH3:2].Cl.[CH3:22][N:23](C)O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:22][NH:23][C:18]([C:4]1[N:3]([CH2:1][CH3:2])[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=1)=[O:19]
Reactant: CN(C)O
Reactant: CCn1cc(C#Cc2cccc(OC)c2)cc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(C#Cc2cccc(OC)c2)cc1C(=O)NC
Reaction time: 4 h
Yield: 93.6 %

Procedure:
This intermediate (2.5 g, 9.28 mmol) was treated with oxalyl chloride (4.1 mL, 46.4 mmol), DMF (2 drops) in methylene chloride (70 mL) and stirred at room temperature for 2 hours to give 1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid chloride (2.7 g, 9.38 mmol) after a usual workup. 1-Ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid chloride (2.7 g, 9.38 mmol) was diluted with methylene chloride (35 mL) and added to a prepared solution of N,O, dimethyl-hydroxylamine hydrochloride (4.6 g, 46.4 mmol) and diisopropyl-ethyl amine (13 mL, 74.3 mmol) in methylene chloride (35 mL) over 5 minutes. The reaction was complete after 4 hours. Solvent was removed in vacuo and the residue was taken back in a mixture of saturated aqueous NH4Cl:H2O (1:1, 150 mL) solution and extracted with ether. Combined ether extracts were washed with brine dried (MgSO4) and filtered. Evaporation and purification by flash chromatography (hexane/ethyl acetate 9/1) gave the title compound as a light yellow oil (2.48 g g, 82% yield), 1H NMR (400 MHZ, CDCl3) □ 1.35-1.37 (t, 3H), 3.31 (s, 3H), 3.67 (s, 3H), 3.78 (s, 3H), 4.29-4.30 (q, 2H), 6.83 (m, 1H), 6.99 (m, 2H), 7.01 (m, 2H), 7.19 (m, 1H), MS m/e (M+H)+ 313.1.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([CH3:19])([CH3:18])[CH2:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:20]Cl>C(O)(=O)C>[Cl:20][C:8]1[CH:7]=[C:6]([C:10]([CH3:19])([CH3:18])[CH2:11][C:12](=[O:17])[C:13]([F:15])([F:16])[F:14])[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cccc2c1OCC2
Reactant: ClCl
Solvent: CC(=O)O
Product: CC(C)(CC(=O)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Yield: 100 %

Procedure:
A solution of 4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one (20.8 g, 76.2 mmol) in 200 mL of acetic acid was treated with a solution of chlorine gas in acetic acid (˜1.19 M). The reaction was monitored by 1H-NMR. The mixture was quenched with 500 mL of water and solid sodium bicarbonate (˜500 g) was added carefully during 1 hour. The mixture was poured onto 500 mL of ethyl acetate. The phases were separated and the aqueous layer was extracted with three 500 mL portions of ethyl acetate. The combined organic layers were washed with two 100 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 23.4 g of 4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one (100%), which was used without purification.
Reaction SMILES: [C:1]1([S:7]([O-:10])(=[O:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH2:12](Br)[CH2:13][OH:14].[OH-].[Na+]>>[C:1]1([S:7]([CH2:12][CH2:13][OH:14])(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)([O-])c1ccccc1
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)(CCO)c1ccccc1
Temperature: 25 °C
Yield: 28.1 %

Procedure:
1,000 ml of an aqueous solution containing 509 g (2.16 mol) of sodium benzenesulfonate (dihydrate) was heated to 80°-90° C. and stirred. To this solution were added at the same time 539 g (4.31 mol) of ethylenebromohydrin and 100 ml of an aqueous solution containing 45 g of sodium hydroxide while maintaining the pH of the reaction solution at 7-8. After the addition was completed, the reaction solution was further stirred for 2 hours at 80°-90° C. and then cooled to room temperature. Then, the reaction solution was extracted with ethyl acetate. The ethyl acetate was concentrated and distilled off under reduced pressure to yield 113 g of the desired product having a boiling point of 172 to 174° C./0.4 mmHg.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C:28]1([N:32](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:31][O:30][CH2:29]1>>[NH2:32][C:28]1([CH2:27][NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:31][O:30][CH2:29]1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=1.2, 7.6 Hz, 1 H), 7.90 (d, J=6.8 Hz, 1 H), 7.66 (s, 1 H), 7.62 (td, J=1.2, 7.6 Hz, 1 H), 7.47-7.43 (m, 2 H), 7.30 (dd, J=1.6, 8.4 Hz, 1 H), 6.20 (s, 1 H), 5.18 (s, 2 H), 4.63 (d, J=6.4 Hz, 2 H), 4.59 (d, J=6.8 Hz, 2 H), 4.59 (brs, 2 H), 3.68 (s, 2 H), 3.59 (t, J=4.4 Hz, 2 H), 2.42 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[Cl:12].[CH2:14]([CH:16]([NH2:19])[CH2:17][CH3:18])[CH3:15]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([NH:19][CH:16]([CH2:17][CH3:18])[CH2:14][CH3:15])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Cl
Reactant: CCC(N)CC
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Cl)c1C(=O)OC
Temperature: 110 °C
Yield: 42.5 %

Procedure:
A mixture of 2,4-dichloro-6-methyl-nicotinic acid methyl ester (2.228 g, 10.13 mmol) and 1-ethyl-propyl amine (1.762 g, 20.26 mmol) in DMSO (4 ml) was heated at 110° C. for 5 hours, then at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentratd to give 1.796 g of crude material. The crude material was purified through silica gel column chromatography using chloroform to 5% methanol in chloroform as eluent to give 1.167 g (43%) of the title compound as a colorless oil. 1H NMR (CDCl3) 657.14 (brs, 1H), 6.27 (s, 1H), 3.86 (s, 3H), 3.27 (m, 1H), 2.33 (s, 3H), 1.3-1.6 (m, 4H), 0.88 (t, 6H) ppm.
Reaction SMILES: N1C=CC=C(C[NH:8][CH2:9][CH2:10][NH2:11])C=1.[N+:12]([CH:15]=[C:16](SC)SC)([O-:14])=[O:13]>C1C=CC=CC=1>[N+:12]([CH:15]=[C:16]1[NH:11][CH2:10][CH2:9][NH:8]1)([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCNCc1cccnc1
Solvent: c1ccccc1
Product: O=[N+]([O-])C=C1NCCN1
Temperature: 25 °C
Yield: 131.8 %

Procedure:
A mixture of N-(3-pyridylmethyl)ethylenediamine (15.1 g), 1-nitro-2,2-bis(methylthio)ethylene (18.2 g) and benzene (150 ml) was refluxed for 4 hours with stirring. The qenerated gas was collected by an alkali trap. The reaction mixture was cooled to room temperature, and filtered to collect crystals. Recrystallization from methanol gave 1-(3-pyridylmethyl)-2-(nitromethylene imidazolidine (17 g) of the following formula as pale yellow crystals. mp. 169°-171° C. ##STR15##
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:11](O)=[O:12]>>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH:11]=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=CO
Product: O=CNc1ccc([N+](=O)[O-])cc1

Procedure:
Was prepared according to Example 2 from 4-nitroaniline and formic acid.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[C:9]([N+:28]([O-:30])=[O:29])=[CH:8][N:7]=1.O.[OH-].[Li+]>CO.O>[C:24]([O:23][C:21]([NH:20][CH:17]1[CH2:18][CH2:19][CH:14]([CH2:13][NH:12][C:10]2[C:9]([N+:28]([O-:30])=[O:29])=[CH:8][N:7]=[C:6]([NH:5][CH2:4][C:3]([OH:31])=[O:2])[N:11]=2)[CH2:15][CH2:16]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)CNc1ncc([N+](=O)[O-])c(NCC2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCC(=O)O)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 124 %

Procedure:
To a suspension of {4-[(4-tert-butoxycarbonylamino-cyclohexylmethyl)-amino]-5-nitro-pyrimidin-2-ylamino}-acetic acid methyl ester (845 mg, 1.9 mmol) in a mixture of MeOH (90 mL) and water (30 mL) was added lithium hydroxide monohydrate (404 mg, 9.6 mmol). The heterogeneous mixture was stirred at room temperature for 1 h. The mixture was concentrated and the resulting residue was acidified to pH 5 using 1M HCl. The product was extracted using ethyl acetate (×3). The combined organic phase was dried over Na2SO4 and concentrated to yield 1.0 g of the crude {4-[(4-tert-butoxycarbonylamino-cyclohexylmethyl)-amino]-5-nitro-pyrimidin-2-ylamino}-acetic acid as a white solid. This product was used for the next reaction without further purification.