Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].N(C(C)(C)C#N)=NC(C)(C)C#N.[C:15]([C:19]1([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][O:20]1)([CH3:18])([CH3:17])[CH3:16].[NH:31]1[CH:35]=[N:34][CH:33]=[N:32]1>CN1CCCC1=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][C:19]([CH2:21][N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)([OH:20])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:25][CH:26]=1
Reactant: CC(C)(C)C1(CCc2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)(C)C(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 120 °C
Yield: 85.4 %

Procedure:
4.15 g (0.103 mole) of sodium hydroxide and a spatula-tip of azo-bis-isobutyronitrile were added to a solution of 71.55 g (0.3 mole) of 2-tert.-butyl-2-(4-chloro-phenyl-ethyl)-oxirane in 10 ml of N-methylpyrrolidone. The mixture was heated to 120° C. and a solution of 20.7 g (0.3 mole) of 1,2,4-triazole was added dropwise in the course of 3 hours, with stirring. The mixture was then stirred at 120° C. for a further hour and then allowed to cool. Thereafter, it was worked up by a procedure in which the N-methyl-pyrrolidone was distilled off at a bath temperature of 100° C. under a pressure of 0.2 mbar and the residue which remained was washed with water and then dried and stirred with 150 ml of benzine. The solid product which deposited was filtered off and dried again. 78.9 g (85.8% of theory) of 1-(4-chloro-phenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-yl-methyl)-pentan-3-ol were obtained in this manner.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:27][O:28][CH2:29][CH2:30][OH:31]>C(Cl)Cl.C(O)(=O)C>[OH:31][CH2:30][CH2:29][O:28]/[N:27]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C:11]3([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH2:13][CH2:12]3)=[N:15][N:16]=2)[N:19]=1)\[CH3:24]
Reactant: CC(=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Reactant: NOCCO
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: C/C(=N\OCCO)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1

Procedure:
A solution of 1-(3-(1-(quinolin-6-yl)cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (30 mg, 0.09 mmol) (59.4) and 2-aminooxy-ethanol hydrochloride (intermediate S) (14 mg, 0.18 mmol) in 4 mL of DCM and 0.5 mL of acetic acid was stirred at 40° C. overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with a EtOAc/methanol gradient to afford the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.84 (t, 1H), 8.30 (d, 1H), 8.25 (d, 1H), 7.93-7.91 (m, 2H), 7.71-7.68 (m, 2H), 7.51 (dd, 1H), 4.73 (t, 1H), 4.23 (t, 2H), 3.65 (q, 2H), 2.02 (s, 3H), 1.78-1.75 (m, 2H), 1.68-1.64 (m, 2H). LCMS (method A): [MH]+=389, tR=4.55 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].ClC1C=C(O)C=CC=1C=O.C(CC(Br)(C)C([O-])=O)C.[F:38][C:39]([F:60])([F:59])[C:40]1[C:45]([C:46](O)=[O:47])=[CH:44][N:43]=[C:42]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[CH:41]=1.COC(=O)C1C(C(F)(F)F)=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:46]([C:45]2[CH:44]=[N:43][C:42]([C:49]3[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:56])[F:57])=[CH:51][CH:50]=3)=[CH:41][C:40]=2[C:39]([F:38])([F:59])[F:60])=[O:47])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)c(Cl)c1
Agent: CCCC(C)(Br)C(=O)[O-]
Agent: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Agent: O=Cc1ccc(O)cc1Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)cc2C(F)(F)F)c(Cl)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-benzaldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 108B]) by saponification in analogy to example 53B]) to give 2-[3-chloro-4-({[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as amorphous light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]3[N:22]=[C:21]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[CH:19][CH:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:31])=[CH:4][N:3]=1.[ClH:32]>O1CCOCC1>[ClH:1].[ClH:32].[NH2:23][C:21]1[N:22]=[C:17]([CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([Cl:31])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:14]=[CH:13][CH:12]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a mixture of tert-butyl [6-(2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-2-yl]carbamate (230 mg, 0.50 mmol) in 1,4-dioxane (1.0 mL) was added 4 M hydrogen chloride in 1,4-dioxane (5.0 mL). The resultant reaction mixture was stirred at rt for 2 hours. The reaction mixture was concentrated under vacuum to give the desired product (212 mg, 98%) as a very hydroscopic light yellow powder. LCMS for C17H16Cl2N5 (M+H)+: m/z=360.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)[CH:16]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccncc2)c1
Yield: 71.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-4-yl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), pyridin-4-ylboronic acid (0.025 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.047 g (71%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-4-yl)benzamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[C:17]([C:32]#[N:33])=[C:16]([Cl:34])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12>Cl.O1CCOCC1>[ClH:34].[ClH:34].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:15]=[C:16]([Cl:34])[C:17]([C:32]#[N:33])=[C:18]4[C:24]=3[O:23][CH2:22][CH2:21][NH:20][CH2:19]4)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C(=O)OC(C)(C)C)C3)c2ncnc(N)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCNC3)c2ncnc(N)c12
Reaction time: 1 h

Procedure:
The crude tert-butyl 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate was dissolved in 4.0 M hydrogen chloride in dioxane (4.0 mL) at room temperature and was stirred for 1 h. The reaction was concentrated in vacuo to give 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile bishydrochloride as an off white solid (0.065 g, 66%). LCMS calculated for C18H19ClN7O (M+H)+: m/z=384.1; found: 384.2.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:6][C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18].S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25].[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[C:12]([N+:24]([O-:26])=[O:25])[CH:13]=2)=[CH:6][C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)n2C)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(=O)n(C)c(=O)n2C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,3-dimethyl-6-(4-methoxyphenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione (4.4 g) in acetic acid (22 ml) were added conc.sulfuric acid (9 ml) and conc. nitric acid (18 ml) under ice-cooling. The mixture was stirred at 5°-10° C. for 1.5 hours and at ambient temperature further for 2 hours. The mixture was poured into ice-water, and stirred. After the aqueous mixture was neutralized with aqueous sodium hydroxide, the resultant precipitates were filtered. The precipitates were washed with water and dried in air to give 1,3-dimethyl-6-(4-methoxy-3-nitrophenyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione (3.67 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([C@@H]1C[C@H](N=[N+]=[N-])CN1)=O)C.[CH3:21][O:22][C:23]([C@@H:25]1[CH2:29][C@H:28]([NH2:30])[CH2:27][N:26]1[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34]C1)=[O:24]>>[CH3:21][O:22][C:23]([C@@H:25]1[CH2:29][C@H:28]([NH2:30])[CH2:27][N:26]1[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:24]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Agent: CCOC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCC1

Procedure:
(2S,4S)-4-Amino-1-cyclopentylmethyl-pyrrolidine-2-carboxylic acid methyl ester was prepared from (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid ethyl ester trifluoroacetate salt in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C13H25N2O2 [(M+H)+] 241, obsd. 241.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1COCC1.C(O)C>[CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NCCCCCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: NCCCCCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of benzaldehyde (1.0 ml, 10.0 mmol) in THF (50 ml) was added with heating at reflux to a solution of 1,6-diaminohexane (5.81 g, 50.0 mmol) and p-toluene sulfonic acid (9.5 1 g, 50.0 mmol) in ethanol (50 ml) and then it was heated to reflux for 3 h under a nitrogen atmosphere. After cooling to room temperature, sodium borohydride (1.13 g, 30.0 mmol) was added to the solution and it was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue dissolved in chloroform. The chloroform phase was washed with water, and dried over magnesium sulphate, the solvent was removed under reduced pressure. The residue was washed with water (25 ml), and it dissolved in chloroform and washed again with water (2×50 ml). Then dried over magnesium sulphate, and the solvent removed under reduced pressure to yield a yellow oil (1.61 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Na].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[O:14][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1ccccc1CBr
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: [Na]
Product: COc1ccccc1COC(=O)Cc1ccc(Cl)cc1

Procedure:
4-Chlorophenylacetic acid, sodium salt, is reacted with 2-methoxybenzyl bromide to obtain 2-methoxybenzyl 4-chlorophenylacetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10](=[O:18])[CH2:9]1.[OH:19][C:20]1C=C2C(C(C3C=CC=CC=3)CC2=O)=C[CH:21]=1>>[C:20]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:9][C:10]2=[O:18])(=[O:19])[CH3:21]
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Reactant: O=C1CC(c2ccccc2F)c2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1ccccc1F
Yield: 85 %

Procedure:
The procedure of Step 3 of Example 1 was repeated except for using 3-(2-fluorophenyl)-2,3-dihydro-6-hydroxyinden-1-one obtained in Step 2 as a starting material instead of 2,3-dihydro-6-hydroxy-3-phenylinden-1-one to obtain the title compound (85%).
Reaction SMILES: O=C1NC(C(NCC2C=CN=C(OCCCC3N=CNN=3)C=2)=O)=NC2SC=C(COCC3C=CC(C(OCC)=O)=CC=3)C1=2.[O:44]=[C:45]1[NH:50][C:49]([C:51](=[O:69])[NH:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][CH2:62][O:63][C:64]3[N:68]=[CH:67][NH:66][N:65]=3)[CH:55]=2)=[N:48][C:47]2[S:70][CH:71]=[C:72]([CH2:73][O:74][CH2:75][C:76]3[CH:86]=[CH:85][C:79]([C:80]([O:82]CC)=[O:81])=[CH:78][CH:77]=3)[C:46]1=2>>[O:44]=[C:45]1[NH:50][C:49]([C:51](=[O:69])[NH:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][CH2:62][O:63][C:64]3[N:68]=[CH:67][NH:66][N:65]=3)[CH:55]=2)=[N:48][C:47]2[S:70][CH:71]=[C:72]([CH2:73][O:74][CH2:75][C:76]3[CH:77]=[CH:78][C:79]([C:80]([OH:82])=[O:81])=[CH:85][CH:86]=3)[C:46]1=2
Reactant: CCOC(=O)c1ccc(COCc2csc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c23)cc1
Agent: CCOC(=O)c1ccc(COCc2csc3nc(C(=O)NCc4ccnc(OCCCc5nc[nH]n5)c4)[nH]c(=O)c23)cc1
Product: O=C(O)c1ccc(COCc2csc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c23)cc1

Procedure:
By a method similar to that in Example 42 and using, instead of ethyl 4-[({[4-oxo-2-({[(2-{[3-(1H-1,2,4-triazol-3-yl)propyl]oxy}pyridin-4-yl)methyl]amino}carbonyl)-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl]methyl}oxy)methyl]benzoate, ethyl 4-({[4-oxo-2-({3-[2-(1H-1,2,4-triazol-3-yloxy)ethoxy]benzyl}carbamoyl)-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl]methoxy}methyl)benzoate obtained in Example 49, the title compound was obtained as a white powder (419.2 mg, 80%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[N:19]3)[CH:9]=1)=[O:7].O>O1CCCC1>[C:6]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[N:19]3)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2cccc3ncccc23)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(-c2cccc3ncccc23)cc1C(=O)O
Reaction time: 30 h
Yield: 65.2 %

Procedure:
0.504 g (12.2 mmol) of lithium hydroxide monohydrate is added to 0.8 g (3.04 mmol) of 3-methoxycarbonyl-4-methyl-1-(quinolin-5-yl)-1H-pyrrole dissolved in 25 mL of tetrahydrofuran and 25 mL of water at a temperature in the region of 20° C. After stirring for 30 hours at the reflux temperature of the solvent, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 20 mL of water and then neutralized with 1 N hydrochloric acid. The mixture is filtered, and the solid residue obtained is dried, giving 0.5 g of 3-carboxy-4-methyl-1-(quinolin-5-yl)-1H-pyrrole in the form of a cream-colored solid, melting above 260° C., which is used directly in the following step.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:11]([N:13]1[CH2:24][CH2:23][CH2:22][C@H:14]1[C:15]([NH:17][CH2:18][C:19]([NH2:21])=[O:20])=[O:16])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:10])[NH2:9].[N+](C1C=CC([O:34][C:35](=O)[C@H:36]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])=CC=1)([O-])=O.CN(C)C=O>C(OCC)C>[ClH:1].[CH2:41]([O:40][C:38]([NH:37][C@H:36]([C:35]([NH:2][C@H:3]([C:11]([N:13]1[CH2:24][CH2:23][CH2:22][C@H:14]1[C:15]([NH:17][CH2:18][C:19]([NH2:21])=[O:20])=[O:16])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:9])[NH2:10])=[O:34])[CH2:48][CH:49]([CH3:50])[CH3:51])=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: N=C(N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of L-arginyl-L-prolyl-glycinamide hydrochloride (from de-protection of 21.2 g. of Nα -benzyloxycarbonyl-L-arginyl-L-prolyl-glycinamide hydrochloride), 17 g. of Nα -benzyloxycarbonyl-L-leucine p-nitrophenyl ester and 85 ml. of dimethylformamide is allowed to stand at 25° C. for 48 hours, warmed to 50° C. for 10 minutes and let stand for six hours at 25° C. The solution is poured slowly into 800 ml. of stirred dry diethyl ether. The sticky solid is separated by decanting, dissolved in 50 ml. of methanol with warming and the solution poured into 500 ml. of stirred ether. The solid is separated and dried at 40° C. under reduced pressure. It is dissolved in 50 ml. of methanol and 450 ml. of chloroform and chromatographed over a column of 170 g. of silica gel (prepared in 10% methanol in chloroform) and eluted with 10 to 20% methanol in chloroform. The desired fractions, as shown by thin layer chromatography, are combined and evaporated to dryness at 40° C. under reduced pressure and the residue is dissolved in 50 ml. of methanol and 25 ml. of ethyl acetate and the solution is dropped slowly into 350 ml. of stirred dry ether. The solid is separated and dried at 40° C. under reduced pressure to give Nα -benzyloxycarbonyl-L-leucyl-L-arginyl-L-prolyl-glycinamide hydrochloride; 11.6 g.; [α]D23 -51.6° (c 1.0, methanol); ultraviolet in methanol λmax 257 E11 3.24.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].O.[OH-].[K+].[CH3:18][N:19]=[C:20](SC)[S:21][CH3:22]>ClCCl>[CH3:18][NH:19][C:20](=[N:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)[S:21][CH3:22]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: CN=C(SC)SC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CNC(=NCCSCc1csc(CN(C)C)n1)SC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask fitted with a condenser, stirrer and thermometer were added 20 g. of the dioxalate salt of 2-dimethylaminomethyl-4-(2-aminoethyl)thiomethylthiazole, and 50 ml. of water. The pH of the solution was adjusted to 6.1 by the addition of 52 ml. of 2N aqueous potassium hydroxide, and 7.5 g. of methylcarbonimidodithioic acid, dimethyl ester, was added. The mixture was stirred at 75° for 3 hours, and was then cooled to ambient temperature. Its pH was adjusted to 6.5 by addition of 3.2 ml. of 2N aqueous potassium hydroxide, and 100 ml. of dichloromethane was added with vigorous mixing. The pH was adjusted to 6.5 again with 1 ml. of 2N aqueous potassium hydroxide, and the organic layer was separated and discarded. The aqueous layer was mixed with 100 ml. of additional dichloromethane, and its pH was adjusted to 13 by addition of 55 ml. of 2N aqueous potassium hydroxide. The organic layer was separated, dried over potassium carbonate and evaporated under vacuum to obtain 13.1 g. of product, which was found by NMR analysis to be substantially identical to that of Example 1. Its purity was 94.6% by high performance liquid chromatographic analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.COC1C=C2C(=CC=1)NCC2.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Cc1ccc2[nH]ccc2c1
Agent: COc1ccc2c(c1)CCN2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CCN2
Yield: 99 %

Procedure:
5-Methylindoline was prepared from 5-methylindole using the procedure described for the preparation of 5-methoxyindoline. 5-Methylindole (11 g, 0.0835 mol) in glacial acetic acid (150 mL) in a 1 L 3-necked flask was reduced at 10–15° C. with sodium cyanoborohydride (15.8 g, 0.251 mol). Extraction with ethyl acetate provided 5-methylindoline (11 g, 0.0832 mol, 99% yield) as a thick oil which was used without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][C:24]([F:27])([F:26])[F:25])[NH2:19]>CS(C)=O.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])[CH:20]=[CH:21][C:22]=1[O:23][C:24]([F:26])([F:27])[F:25]
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(Nc2ccc(OC(F)(F)F)c(Cl)c2)c1
Yield: 37.6 %

Procedure:
A solution of methyl 3-fluoro-4-nitrobenzoate (1.99 g, 10 mmol) and 3-chloro-4-(trifluoromethoxy)aniline (4.23 g, 20 mmol) in dimethylsulfoxide (10 mL) was stirred at 160° C. for 2 days. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) and recrystallized from hexane/ethyl acetate to give the title compound (1.47 g, yield 38%) as orange crystals.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]2[NH:7][C:8]([CH2:10][C:11]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]4[C:12]=3[CH:13]=[CH:14][N:15]4C(OC(C)(C)C)=O)=[N:9][C:5]=2[CH:4]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CO>[CH3:21][O:20][C:19]1[C:11]([CH2:10][C:8]2[NH:7][C:6]3[CH:30]=[CH:31][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)=[C:12]2[C:16](=[C:17]([CH3:22])[CH:18]=1)[NH:15][CH:14]=[CH:13]2
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 58 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((5-cyano-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (878 mg, 2.108 mmol) in THF (12 mL) and MeOH (12 mL) was added Cs2CO3 (3.4 g, 10.54 mmol). The mixture was stirred at 58° C. for 1 hour. The reaction mixture was cooled to room temperature, concentrated and purified by flash chromatography (DCM:EtOAc) to provide the title compound. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 8.24 (br. s., 1H) 7.86 (s, 1H) 7.59 (d, J=8.34 Hz, 1H) 7.46-7.54 (m, 1H) 7.30 (t, J=2.91 Hz, 1H) 6.87 (s, 1H) 6.71 (m, 1H) 4.60 (s, 2H) 4.03 (s, 3H) 2.53 (s, 3H). HRMS calcd. for C13H16N4O (M+H)+ 317.1397. found 317.1400.