Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][C:21]#[N:22])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1[nH]c2cc(Cl)ccc2c(CCc2nnn[nH]2)c1-c1ccccc1
Temperature: 150 °C
Reaction time: 48 h
Yield: 9.8 %

Procedure:
To a solution of 7-chloro-4-(2-cyanoethyl)-3-phenyl-quinolin-2(1H)-one (Example 39, 0.45 g) in 1-methyl-2-pyrrolidinone (50 ml) under nitrogen at room temperature, was added sodium azide (0.28 g) followed by triethylamine hydrochloride (0.30 g). The reaction mixture was heated to 150° C. and stirred for 48 h. After allowing to cool, the mixture was poured into water (100 ml), acidified to pH 1 with concentrated HCl and extracted with ethyl acetate (3×75 ml). The combined organic layers were extracted with 1N sodium hydroxide (3×75 ml) and the combined aqueous phases were washed with diethyl ether (2×75 ml), then acidified to pH 1 using concentrated HCl. The aqueous layer was extracted with ethyl acetate (3×75 ml) and the combined organic layers were dried (MgSO4), filtered and the solvent was removed in vacuo to leave a solid residue. Recrystallisation from a water/methanol mix then from ethyl acetate gave the title compound (0.05 g). Mp 231°-233° C. Found: C, 61.31; H, 4.20; N, 19.41; C18H14N5OCl. 0.1 H2O requires C, 61.14; H, 4.05; N, 19.81%. δ (360 MHz, DMSO-d6) δ 3.05 (4H, bs, CH2CH2Tet)), 7.10-7.42 (7H, m, Ph+6-H+8-H), 7.86 (1H, d, J=8.73 Hz, 5-H), 12.00 (1H, bs, NH). m/z (CI+), 352, (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]([NH:15][NH2:16])=[O:14])[CH:12]=[C:6]2[C:5]=1[NH:17][C@@H:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:19]1([CH3:32])[CH3:31])(=[O:3])[NH2:2].N1([C:38](N2C=CN=C2)=[S:39])C=CN=C1.[CH2:45](N(CC)CC)C.IC>O1CCCC1>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:14][C:45]([S:39][CH3:38])=[N:16][N:15]=3)[CH:12]=[C:6]2[C:5]=1[NH:17][C@@H:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:19]1([CH3:32])[CH3:31])(=[O:3])[NH2:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)NN)cc23)C(C)(C)C1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nnc(-c2cc3c(N[C@@H]4CCN(C(=O)OC(C)(C)C)CC4(C)C)c(C(N)=O)cnn3c2)o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
A solution of (R)-tert-butyl 4-((3-carbamoyl-6-(hydrazinecarbonyl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (380 mg, 0.853 mmol) and di(1H-imidazol-1-yl)methanethione (175 mg, 0.981 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 10 min then heated to reflux for 100 min. After cooling to room temperature, triethylamine (0.357 mL, 2.56 mmol) and iodomethane (0.107 mL, 1.706 mmol) were added. The resulting mixture was stirred at room temperature for 5 h. The tetrahydrofuran solvent was evaporated in vacuo. The residue was triturated with water. The solid product was collected by filtration to give (R)-tert-butyl 4-((3-carbamoyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3,3-dimethylpiperidine-1-carboxylate as white solid (0.404 g, 94% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 10.78 (d, J=8.4 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H), 7.94 (s, 1H), 5.50 (br. s., 2H), 4.01 (dd, J=9.4, 5.8 Hz, 2H), 3.72 (br. s., 1H), 3.18 (br. s., 1H), 2.91 (br. s., 1H), 2.80 (s, 3H), 2.06 (d, J=14.3 Hz, 1H), 1.89-1.75 (m, 1H), 1.49 (s, 9H), 1.12 (s, 3H), 1.05 (s, 3H); MS (ES+) m/z: 502.3 (M+H); LC retention time: 4.241 min (analytical HPLC Method H).
Reaction SMILES: Br[C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:24])=[N:7]2.CC1(C)C(C)(C)OB([C:33]2[CH:42]=[CH:41][C:40]3[O:43][CH2:44][CH2:45][N:38]4[C:39]=3[C:34]=2[CH2:35][CH2:36][CH2:37]4)O1.C(COC)OC.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=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>[C:19]([O:18][C@@H:12]([C:11]1[C:2]([C:33]2[CH:42]=[CH:41][C:40]3[O:43][CH2:44][CH2:45][N:38]4[C:39]=3[C:34]=2[CH2:35][CH2:36][CH2:37]4)=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:23])[N:7]=[C:6]([CH3:24])[CH:5]=[CH:4]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2ccc3c4c2CCCN4CCO3)OC1(C)C
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1-c1ccc2c3c1CCCN3CCO2
Temperature: 80 °C

Procedure:
Preparation of (2S)-ethyl 2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-8-yl)quinolin-6-ypacetate: A Smith process vial was charged with (S)-ethyl 2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (52 mg, 0.133 mmol, 1 eq.), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinoline (48 mg, 0.159 mmol.), Pd(PPh3)4 (15 mg, 10%) and flushed with nitrogen. Dimethoxyethane (1.6 mL) and 2 M K2CO3 (0.24 mL, 0.48 mmol) was added. The reaction was heated in oil bath at 80° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (2S)-ethyl 2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-8-yl)quinolin-6-yl)acetate as atropisomer mixture (39 mg, 60%). LCMS-ESI+: calcd for C30H37N2O4: 489.52 (M+H+). Found: 489.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C@H:25]5[CH2:29][CH2:28][CH2:27][NH:26]5)[N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH2:32]=O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C@H:25]5[CH2:29][CH2:28][CH2:27][N:26]5[CH3:32])[N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)cc2cnn1Cc1cccc(OC[C@H]2CCCN2)n1
Reactant: C=O
Solvent: ClCCl
Solvent: CO
Product: CN1CCC[C@@H]1COc1cccc(Cn2ncc3cc(-c4ccc(Cl)cc4)sc3c2=O)n1

Procedure:
2-(4-Chlorophenyl)-6-({6-[(2R)-pyrrolidin-2-ylmethoxy]pyridin-2-yl}methyl)thieno[2,3-d]pyridazin-7(6H)-one (0.340 g, 0.75 mmol), formaldehyde(aq.) 36% (0.23 mL, 2.25 mmol) and MacroPorous-triacetoxyborohydride (0.88 g, 2.25 mmol) were shaked in DCM/MeOH (1:1, 4 mL) at room temperature for 3 hours. The reaction mixture was filtrated, concentrated in vacuo and purified by flash chromatography using a gradient with EtOAc:MeOH:TEA (1:0.1:0.01) in n-heptane, which gave the product as an solid. Yield: 0.207 g (59%). 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.55-7.61 (m, 2H), 7.37-7.48 (m, 4H), 6.69 (d, 1H, J=7.27 Hz), 6.59 (d, 1H, J=8.26 Hz), 5.45 (s, 2H), 4.21-4.27 (m, 1H), 4.06-4.14 (m, 1H), 2.97-3.04 (m, 1H), 2.41-2.52 (m, 1H), 2.34 (s, 3H), 2.11-2.21 (m, 1H), 1.78-1.91 (m, 1H), 1.54-1.78 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 163.7, 157.4, 153.9, 152.3, 140.3, 139.2, 136.6, 136.0, 133.3, 131.4, 129.8, 128.2, 118.9, 114.3, 110.0, 68.3, 64.4, 57.9, 56.0, 41.8, 28.7, 23.1. MS (ESI+) 467.0 (M+1H+).
Reaction SMILES: [N:1]1([C:7](=[NH:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]([C:25](OCC)=[O:26])([C:20](OCC)=[O:21])[CH:11]([C:15]([O:17]CC)=[O:16])[CH2:12][CH2:13][CH3:14].C[O-].[Na+]>CO>[OH:21][C:20]1[C:10]([CH:11]([CH2:12][CH2:13][CH3:14])[C:15]([OH:17])=[O:16])=[C:25]([OH:26])[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: N=C(N)N1CCCCC1
Reactant: CCCC(C(=O)OCC)C(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(C(=O)O)c1c(O)nc(N2CCCCC2)nc1O

Procedure:
To a solution of piperidine-1-carboximidamide (dimer complexated with H2SO4) (1.32 g; 10.4 mmol) and triethyl pentane-1,1,2-tricarboxylate (3 g; 10.4 mmol) in methanol (15 mL) was slowly added a solution of sodium methoxide in methanol (25% w:w) (4.76 mL; 20.81 mmol) and the reaction was heated to reflux for 18 h. The volatiles were removed under reduced pressure and the crude residue was used as such in the next reaction.
Reaction SMILES: COC(=O)N.[CH3:6][O:7][C:8](=[O:35])[NH:9][CH:10]([C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]1[NH:22][C:23]([C:26]#[C:27][C:28]2[CH:33]=CC(Br)=CC=2)=[CH:24][N:25]=1)=[O:15])[CH:11]([CH3:13])[CH3:12].[CH3:36][O:37][C:38](=[O:68])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][C:53]([C:56]2[CH:65]=[CH:64][C:63]3[C:58](=[CH:59][CH:60]=[C:61]([C:66]#[CH:67])[CH:62]=3)[CH:57]=2)=[CH:54][N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42].COC(=O)N[CH:73](C(N1CCCC1C1NC(C#C)=CN=1)=O)[CH:74](C)C>>[CH3:36][O:37][C:38](=[O:68])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][C:53]([C:56]2[CH:65]=[CH:64][C:63]3[C:58](=[CH:59][CH:60]=[C:61]([C:66]#[C:67][C:27]4[CH:28]=[CH:33][C:24]5[N:25]=[C:21]([CH:17]6[CH:18]7[CH2:19][CH:20]([CH2:73][CH2:74]7)[N:16]6[C:14](=[O:15])[CH:10]([NH:9][C:8]([O:7][CH3:6])=[O:35])[CH:11]([CH3:13])[CH3:12])[NH:22][C:23]=5[CH:26]=4)[CH:62]=3)[CH:57]=2)=[CH:54][N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(Br)cc2)[nH]1)C(C)C
Reactant: C#Cc1ccc2cc(-c3cnc(C4CCCN4C(=O)C(NC(=O)OC)C(C)C)[nH]3)ccc2c1
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Agent: COC(N)=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(C#Cc4ccc5nc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]c5c4)ccc3c2)[nH]1)C(C)C

Procedure:
Title compound was prepared according to the method employed to prepare Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example CT), substituting {1-[3-(6-Bromo-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carbonyl]-2-methyl-propyl]-carbamic acid methyl ester for (1-{2-[5-(4-bromo-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester and (1-{2-[5-(6-Ethynyl-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for {1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester. NMR (MeOH-d4, 400 MHz) δ: 8.19-8.11 (m, 1H), 8.01-7.99 (m, 1H), 7.86-7.71 (m, 3H), 7.57-7.39 (m, 3H), 7.02-6.99 (m, 1H); MS (ESI) m/z 813 [M+H]+.
Reaction SMILES: [K].[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:4])[CH3:3].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>>[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Br:13])=[CH:8][CH:7]=1)([CH3:4])[CH3:3]
Reactant: CC(C)Oc1ccc(O)cc1
Reactant: BrCCCCCCBr
Agent: [K]
Product: CC(C)Oc1ccc(OCCCCCCBr)cc1

Procedure:
The intermediate 6-(4-isopropoxyphenoxy)hexyl bromide was prepared from the potassium salt of 4-isopropoxyphenol and 1,6-dibromohexane.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.F[C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([CH:39]=1)[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:4]2[C:5]([N:24]([C:30]3[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([CH:39]=3)[C:35]([O:37][CH3:38])=[O:36])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 70 °C
Reaction time: 72 h
Yield: 83.3 %

Procedure:
A mixture of 55.0 g (123 mmol) of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide, 36.7 g (184 mmol) of methyl 5-fluoro-2-nitrobenzoate, and 39.1 g (369 mmol) of sodium carbonate in 400 mL of DMF was heated to 70° C. with vigorous stirring. After 72 hours LCMS indicated nearly complete reaction. The mixture was cooled to RT, diluted with 300 mL of EtOAc, and filtered through a bed of celite to remove solids. The filter cake was washed with EtOAc until the filtrate ran colorless which gave a total filtrate volume of 1.2 L. The filtrate was transferred to a separatory funnel, partitioned with 1.4 L of 5% aqueous NaCl, and the phases separated. The aqueous solution was extracted with two additional 300 mL portions of EtOAc. The combined EtOAc solutions were washed with 95% aqueous NaCl (2×), saturated aqueous NaCl (1×), dried over sodium sulfate and concentrated to approximately 200 mL by rotary evaporation. At this point a solid began to crystallize. The suspension was diluted with 200 mL of DCM and the suspension stirred overnight. The suspension was then cooled in an ice water bath for 2 hours and the solid collected by vacuum filtration. The filter cake was washed twice with cold 1:1 EtOAc/DCM, suction air dried for 30 minutes and then dried in vacuo overnight to afford 59.6 g (83%) of methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (q, J=4.42 Hz, 1H) 8.13 (d, J=9.07 Hz, 1H) 8.08 (s, 1H) 7.93-8.01 (m, 2H) 7.57 (d, J=2.63 Hz, 1H) 7.53 (dd, J=9.07, 2.73 Hz, 1H) 7.38-7.46 (m, 2H) 7.29 (s, 1H) 3.83 (s, 3H) 3.60 (s, 3H) 2.85 (d, J=4.59 Hz, 3H) 1.87-2.04 (m, 1H) 0.87 (m, 2H) 0.73 (m, 1H) 0.46 (m, 1H). LCMS(ESI): 582 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[CH3:2].N1C(C)=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:26].[CH3:27]I>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH:16][CH3:27])[C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:26]=1
Reactant: Cc1cccc(C)n1
Reactant: CCOC(=O)CCNC(=O)c1cc(I)ccc1N
Reactant: CI
Solvent: CN(C)C=O
Product: CNc1ccc(I)cc1C(=O)NCCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A magnetically stirred solution of 0.848 gram of N-(2-amino-5-iodobenzoyl)-b-alanine ethyl ester (2.0 mmol), 0.35 mL 2,6-lutidine (3.0 mmol), 0.19 mL methyl iodide (3.0 mmol), and 15 mL dimethylformamide was heated to 50° C. for 15 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was dissolved in 75 mL ethyl acetate and washed 1×50 mL 10% citric acid, 1×50 mL sat. sodium bicarbonate, 1×50 mL brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was further purified by column chromatography, using silica gel, eluting with a solvent gradient of 35/65 ethyl acetate/hexane to 65/35 ethyl acetate/hexane (TLC, SiO2, 1:1 EtOAc/hexane, Rf =0.84, un positive) to yield 305 mgs (35%) of N-(2-methylamino-5-iodobenzoyl)-b-alanine benzyl ester. 1H NMR (CDCl3, dTMS) 7.56 (2H, m, Ar-H o,p-CON), 7.43 (1H, bq, 3JHH =5 Hz, NHMe), 7.38-7.32 (5H, s, ArH Ph), 6.62 (1H, bt, 3JHH =6 Hz, CONH), 6.42 (1H, d, 3lJHH =9 Hz, Ar-H m-CON), 5.16 (2H, s, OCH2), 3.64 (2H, q, 3 l JHH =6 Hz, NCH2), 2.81 (3H, d, 3JHH =5 Hz, NCH3), 2.64 (2H, t, 3JHH =6 Hz, CH2CO2). 13C NMR (CDCl3, dTMS) 172.4, 168.4, 148.8, 141.0, 135.5, 128.7, 128.4, 128.3, 117.3, 113.4, 74.1, 66.7, 35.2, 34.0, 29.6.
Reaction SMILES: C(O[C:4](=[O:7])[CH2:5][Br:6])C.[CH2:8]([N:10]([CH2:15][CH3:16])[C:11](=[O:14])[CH2:12][Br:13])[CH3:9]>>[CH2:8]([N:10]([CH2:11][CH2:12][Br:13])[CH2:15][CH3:16])[CH3:9].[C:11]([NH:10][C:4](=[O:7])[CH2:5][Br:6])(=[O:14])[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: CCN(CC)C(=O)CBr
Product: CC(=O)NC(=O)CBr
Product: CCN(CC)CCBr

Procedure:
When ethylbromoacetate in the above procedure is replaced with N,N-diethyl-α-bromoacetamide; N,N-diethylaminoethyl bromide or N-acetyl-α-bromoacetamide, then the corresponding products are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:12]([NH:13]C(OC(C)(C)C)=O)=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:10][CH:9]=1)(C)(C)C.Br.CCOCC>C(O)(=O)C>[C:21]1([C:11]2[S:10][CH:9]=[C:8]([NH2:7])[C:12]=2[NH2:13])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1csc(-c2ccccc2)c1NC(=O)OC(C)(C)C
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1csc(-c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To a solution of compound 59 in glacial acetic acid (102 μL) was added a 30% solution of HBr in acetic acid (102 μL). The mixture was stirred for 16 h at r.t. and Et2O (10 mL) was added. The precipitate was collected by filtration and immediately dissolved in water, neutralized by addition of 2N aqueous NaOH and the precipitate was extracted with Et2O. The organic layer was dried over MgSO4 and concentrated in vacuum affording the title compound 60 (34 mg, 69% yield). This procedure is essentially as described in Brugier et al., Tetrahedron, 30: 10331-10344 (1997), which is incorporated by reference in its entirety. 1H NMR: (CDCl3) δ(ppm): 7.49 (dd, J=8.4, 1.4 Hz, 2H), 7.41 (t, J=7.6 Hz, 2H), 7.26 (dd, J=10.2, 7.2 Hz, 1H), 6.22 (s, 1H), 3.51 (bs, 4H). m/z: 191.3 (MH+).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:24](O)[CH2:25][CH2:26][CH3:27]>C(Cl)Cl.CN(C=O)C>[CH2:24]([O:5][C:4](=[O:6])[C:3]([CH3:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Reactant: CCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)C(C)(C)C(F)(F)F
Reaction time: 2 h

Procedure:
3,3,3-Trifluoro-2,2-dimethyl-propionic acid (3.0 g, 19.2 mmol) and a drop of DMF are dissolved in 30 mL of DCM and treated dropwise at RT with oxalyl chloride (1.85 mL, 21.1 mmol). After 2 h gas evolution ceases and the mixture is treated slowly with triethyl amine (5.36 mL, 38.4 mmol) followed by n-butanol (2.1 mL, 23 mmol). The mixture is stirred over night, the solvent evaporated and the residue stirred with hexanes. The solid is filtered off and the filtrate is evaporated to a brown-red oil. Kugelrohr distillation (10 mbar, 60-80° C. oven temperature) gives the title compound a colorless liquid.
Reaction SMILES: [C:1]([S-:3])#N.[K+].[C:5]([NH:12][C@H:13]([C:17]([N:19]1[CH2:24][CH2:23]C=[CH:21][CH2:20]1)=[O:18])[CH:14]([CH3:16])[CH3:15])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>O.CCO>[S:3]1[CH:1]2[CH:21]1[CH2:20][N:19]([C:17](=[O:18])[C@@H:13]([CH:14]([CH3:15])[CH3:16])[NH:12][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:24][CH2:23]2
Reactant: N#C[S-]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC=CCC1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC2SC2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2.91 g of KSCN in 3 ml of H2O are added to a mixture of 5.96 g of 3,4-epoxy-N—(N-BOC-valyl-1,2,5,6-tetrahydropyridine in 10 ml of absolute EtOH and the mixture obtained is stirred for 72 hours at RT. The mixture obtained is subjected to aqueous extraction, the solvent of the organic phase obtained is evaporated and the evaporation residue is subjeted to chromatography. 3,4-Epithio-N(N-BOC-(R)-valyl)-piperidine is obtained. Melting point: 69.71°
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Cl:10][CH2:11][C:12](Cl)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:10][CH2:11][C:12]([C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:13]
Reactant: O=C(Cl)CCl
Reactant: c1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(CCl)c1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 7-azaindole (10 g) and chloroacetyl chloride (7.4 mL, 1.1 eq.) are dissolved in carbon disulfide, treated with aluminum chloride (85 g, 7.5 eq.), heated at reflux temperature for 2 h, treated with chloroacetyl chloride (7.4 mL, 1.1 eq.), continued heating at reflux temperature for a further 2 h, cooled to room temperature and decanted to remove the solvent. The sediment is cooled to 0° C., quenched with ice water, treated with sodium carbonate to pH 9 and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give the title ethanone, 12.5 g (75% yield), identified by HPLC and mass spectral analyses.
Reaction SMILES: [CH2:1]=O.[NH:3]1[CH2:9][CH2:8][CH2:7][C@H:4]1[CH2:5][OH:6].[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.[OH-].[Na+]>C(O)(=O)C>[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:1][N:3]2[CH2:9][CH2:8][CH2:7][C@H:4]2[CH2:5][OH:6])=[CH:12]1
Reactant: OC[C@@H]1CCCN1
Reactant: Cn1ccc2ccccc21
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1cc(CN2CCC[C@H]2CO)c2ccccc21
Reaction time: 0.08 h
Yield: 83 %

Procedure:
To a mixture of formalin (0.33 ml, 48% in H2O) and acetic acid (0.9 ml) was added L-prolinol (0.43 g) with stirring under ice-cooling. After 5 min, 1-methyl indole (0.56 g) was added dropwise to the above reaction mixture, and stirring was continued for 2 h. At the end of this time, reaction mixture was basified with 2N NaOH; the oily residue was extracted with ethyl acetate, dried (Na2SO4), and the solvent was evaporated to dryness to give the title compound (0.87 g, 83%), as a white solid, mp. 46°-48° C.
Reaction SMILES: [C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:41])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 76 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 76% of theory, Rf value: 0.17 (silica gel; dichloromethane/ethanol=4:1) C27H27N5O4 (485.6) ##EQU21##
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[C:14]([F:24])[CH:13]=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:26]1>CN(C)C=O>[C:1]([O:5][C:6]([C:8]1[N:9]([CH3:26])[C:10]2[C:15]([C:16]=1[NH:17][C:18]1[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=1)=[C:14]([F:24])[CH:13]=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1[nH]c2cccc(F)c2c1Nc1ccncc1
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1c(C(=O)OC(C)(C)C)c(Nc2ccncc2)c2c(F)cccc21

Procedure:
Follow the procedure of Example 24 but start with 4-fluoro-3-(4-pyridinylamino)-1H-indole-2-carboxylic tert-butyl ester, but substitute tetrahydrofuran for dimethylformamide to obtain the title compound: ESI/MS 342 (M+H); HPLC: Rt=1.41 min.