Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:8][NH:7][CH2:6][C@H:5]1[NH:9][C:10]1[C:15]([CH2:16][CH3:17])=[N:14][CH:13]=[C:12]([CH2:18][CH3:19])[N:11]=1)[CH3:2].C(N(CC)CC)C.Cl[C:28]([O:30][CH3:31])=[O:29].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:16]([C:15]1[C:10]([NH:9][C@H:5]2[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:8][N:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]2)=[N:11][C:12]([CH2:18][CH3:19])=[CH:13][N:14]=1)[CH3:17]
Reactant: COC(=O)Cl
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)cnc1CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)cnc1CC
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine (4.50 g, 17 mmole) in CH2Cl2 (0.1 M, 170 mL) under N2 at 0° C. was added triethyl amine (7.09 mL, 3.0 eq.). Methyl chloroformate (1.44 mL, 1.1 eq.) was added drop-wise over 15 min. After 1 hour, the reaction mixture was poured into saturated aqueous NaHCO3 (150 mL). The aqueous layer was extracted with CH2Cl2 (1×200 ml), dried with MgSO4, filtered and concentrated. Purification with Biotage MPLC (40 g, 10-50% ethyl acetate in heptane gradient) provided 5.35g (98%) of methyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate as an oil. IR (liq.) 2972, 2937, 2877, 2338, 1937, 1708, 1581, 1546, 1499, 1453, 1392, 1189, 1174, 1135, 1103 (s) cm−1 HRMS (ESI) calcd for C16H26N4O3+H1 323.2083. found 323.2089. Anal. Calcd for C16 H26 N4O3: C, 59.61; H, 8.13; N, 17.38. Found: C, 59.23; H, 8.35; N, 17.33.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)=[O:10].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)=[C:20]([CH3:25])[CH:19]=1)=[O:10]
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc(C(=O)NCCCCCC(=O)Nc2ccccc2N)ccc1Br
Product: Cc1cc(C(=O)NCCCCCC(=O)Nc2ccccc2N)ccc1-c1ccncc1
Yield: 63 %

Procedure:
The procedure of Example 81 was repeated except for using N-(5-(2-aminophenylcarbamoyl)pentyl)-4-bromo-3-methylbenzamide instead of N-(5-(2-aminophenylcarbomoyl)pentyl)-3-bromo-2-methylbenzamide, and 4-pyridinyl boronic acid instead of phenyl boronic acid to obtain the title compound (32 mg, 63%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(Br)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-bromobenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-bromophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1.CI.[CH3:21]C(C)=O.C(=O)=O.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1
Reactant: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Reactant: CC(C)=O
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
2-Chloro-9-cyclopentyl-5,7,8,9-tetrahydro-6H-pyrimido [4,5-b][1,4] diazepin-6-one (318 mg, 0.0012 mol) and MeI (88 μl, 0.0014 mol, 1.18 eq) were added to DMF (5 ml) and the solution cooled to −10° C. using acetone/dry ice before the addition of NaH (30 mg, 0.0013 mol, 1.07 eq). The RM was then stirred at 0° C. for 30 min and rt for 30 min. The RM was concentrated and the product extracted using EtOAc/H2O. The organic extracts were combined, washed with sat NaCl, dried using MgSO4, filtered and the filtrate evaporated under reduced pressure and further dried in vacuo to give the product as a purple oily residue (252 mg, 75%); Rt=13 min (Vydac 1); MS+ve: 281.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([CH2:13][C:14]([O:16]CC)=O)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[CH3:21][CH:22]([CH3:37])[CH2:23][CH2:24][N:25]1[C:30]2[N:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28](=O)[O:27]C1=O.[H-].[Na+].C(O)(=O)C>C1COCC1>[OH:27][C:28]1[C:29]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:25]([CH2:24][CH2:23][CH:22]([CH3:37])[CH3:21])[C:14](=[O:16])[C:13]=1[C:8]1[NH:7][C:6]2[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[S:10](=[O:11])(=[O:12])[N:9]=1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2cc(OC)ccc2N1
Reactant: CC(C)CCn1c(=O)oc(=O)c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 0 °C
Yield: 79.9 %

Procedure:
To a solution of the product of Example 183B (0.5 g, 1.6 mmol) and the product of Example 12A (0.375 g, 1.6 mmol) in anhydrous THF (16 mL) under nitrogen at 0° C. was added sodium hydride (95%, 0.162 g, 6.4 mmol). The reaction was heated at reflux for 4 hours, cooled to 0° C., and treated dropwise with glacial acetic acid (3 mL). The resulting mixture was heated at reflux for 2 hours, cooled to 25°, and diluted with ice water (150 mL). The resulting precipitate was collected by filtration, washed with water and recrystallized from dioxane/water to give the title compound (566 mg, 80%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. MS (ESI−) m/z 441 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (d, J=6.62 Hz, 6 H) 1.48 (m, 2 H) 1.64 (m, 1 H) 3.82 (s, 3 H) 4.29 (m, 2 H) 7.16 (m, 4 H) 8.36 (dd, J=7.54, 2.02 Hz, 1 H) 8.52 (dd, J=4.60, 2.02 Hz, 1 H) 15.86 (s, 1 H).
Reaction SMILES: OC1C=CC(CN[C:8]([C:10]2([CH3:15])[CH2:14][S:13][S:12][CH2:11]2)=[O:9])=CC=1OC.Cl.[NH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][CH3:32])[CH:25]=1>>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][NH:21][C:8]([C:10]2([CH3:15])[CH2:14][S:13][S:12][CH2:11]2)=[O:9])=[CH:25][C:26]=1[O:31][CH3:32]
Reactant: COc1cc(CCN)ccc1O
Reactant: COc1cc(CNC(=O)C2(C)CSSC2)ccc1O
Agent: Cl
Product: COc1cc(CCNC(=O)C2(C)CSSC2)ccc1O
Yield: 64 %

Procedure:
Same method as for Compound 16 with 4-(2-aminoethyl)-2-methoxyphenol hydrochloride. 320 mg of a yellow solid are obtained (yield=64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=O)[CH:4]=1.Cl.N1C=CC=CC=1.[K+].[C:19]([O:25][CH3:26])(=[O:24])[CH2:20]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[CH:20][C:19]([O:25][CH3:26])=[O:24])[CH:4]=1
Reactant: COC(=O)CC(=O)[O-]
Reactant: COc1ccnc(C=O)c1
Agent: Cl
Agent: [K+]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC(=O)C=Cc1cc(OC)ccn1
Temperature: 120 °C

Procedure:
A mixture of 45 g of 4-methoxypyridine-2-carbaldehyde (Ashimori et al., Chem. Pharm. Bull. 38, 2446–2458 (1990)), 75.80 g of pyridine hydrochloride, 102.45 g of monomethyl malonate potassium salt and 4.1 ml of piperidine in 700 ml of pyridine are slowly heated, with stirring, to 120° C. When the evolution of gas starts, the heating source is temporarily removed to stop the reaction from becoming too violent. Once the reaction has subsided, the mixture is stirred at 120° C. for a further 2.5 h, and the pyridine is then distilled off under reduced pressure. The residue is partitioned between ethyl acetate/water and the organic phase is washed with water and dried. The residue obtained after concentration is chromatographed on a silica gel column using ethyl acetate/petroleum ether 2:1. This initially gives 43.2 g of the title compound as a yellow oil which crystallizes on standing and then shows a m.p. of 80–82° C. The mass spectrum shows the molecular peak MH+ at 194 Da.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1>>[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:13]1
Reactant: N#Cc1ccccc1F
Reactant: OCC1CCCNC1
Product: N#Cc1ccccc1N1CCCC(CO)C1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 3-(hydroxymethyl)piperidine.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)[CH2:2][CH2:3][CH3:4].[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:8](/[CH:9]=[CH:17]/[N+:14]([O-:16])=[O:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[N+](=O)[O-]
Reactant: CCCCOc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCCCOc1cccc(/C=C/[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 74.8 %

Procedure:
A mixture of 3-butoxy-benzaldehyde (4.23 g, 23.7 mmol) described in Manufacturing Example 65-1-1, nitromethane (2.55 mL, 47.7 mmol), ammonium acetate (2.74 g, 35.6 mmol) and acetic acid (40 mL) was stirred for 5 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-1:1) to obtain the title compound (3.92 g, 75%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[Cl:24][C:25]1[CH:26]=[C:27]([S:34](Cl)(=[O:36])=[O:35])[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]>C(Cl)Cl>[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:34]([C:27]2[CH:28]=[CH:29][C:30]([N+:31]([O-:33])=[O:32])=[C:25]([Cl:24])[CH:26]=2)(=[O:36])=[O:35])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Diisopropylethylamine (1.74 ml, 9.98 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.25 g, 1.25 mmol) in DCM (5 ml) at room temperature. To this mixture was added 3-chloro-4-nitrobenzene sulfonyl chloride (0.32 g, 1.25 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml), the organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: % EtOAc: % Heptane) to give the title compound (0.44 g, 84% yield) as a white solid. δH (500 MHz, DMSO) 7.97-8.12 (m, 3 H) 6.93 (d, J=7.72 Hz, 1 H) 3.64 (d, J=12.77 Hz, 2 H) 3.43 (d, J=3.94 Hz, 2 H) 2.88-3.00 (m, 2 H) 1.78 (d, J=10.40 Hz, 2 H) 1.25-1.46 (m, 11 H). Tr=2.22 min, m/z (ES+) (M+Na)+ 442.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)=[O:9])([CH3:4])[CH3:3].[H][H]>C(O)C.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1)=[O:9])([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(C(=O)NCc2cccc(N)c2)cc(C(C)(C)C)c1O
Yield: 42.8 %

Procedure:
In a 250 ml Parr flask, 2.40 g (6.2 mmoles) of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide is dissolved in 45 ml of an absolute ethanol/TXF mixture (1/2) in the presence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen, at 30° C., for three hours. After filtration on celite, the filtrate is concentrated to dryness and the residue is purified on a silica column (eluant: heptane/ethyl acetate: 60/40). The pure fractions are collected and concentrated under reduced pressure to produce 0.94g (45%) of a white powder. Melting point: 171-172° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1OS(C)(=O)=O)(=O)[CH3:2].[CH3:16][O:17][CH2:18][CH2:19][CH2:20][NH:21][NH2:22].C([O-])(=O)C.[NH4+].O>CC1C=CC=CC=1C>[Br:10][C:7]1[CH:6]=[C:5]2[C:4]([C:1]([CH3:2])=[N:22][N:21]2[CH2:20][CH2:19][CH2:18][O:17][CH3:16])=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Reactant: COCCCNN
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1C
Product: COCCCn1nc(C)c2ccc(Br)cc21
Temperature: 25 °C

Procedure:
A mixture of 10.90 g methanesulfonic acid 2-acetyl-5-bromo-phenyl ester, 7.75 g of (3-methoxy-propyl)-hydrazine and 7.17 g of ammonium acetate in 100 ml of o-xylene is refluxed for 3 days with continuous separation of the water which is formed during the reaction. The reaction mixture is then cooled to room temperature and concentrated by evaporation. The title compound is obtained as an orange-yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.38 (1:1 EtOAc-heptane). Rt=4.52 (gradient I).
Reaction SMILES: [C@@H:1]12[CH2:6][C@@H:5]1[CH2:4][C@H:3]([C:7]([NH:9][C:10]1([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH2:12][CH2:11]1)=[O:8])[NH:2]2.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:2]1[C@@H:3]([C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:11][CH2:12]2)=[O:8])[CH2:4][CH:5]2[CH:1]1[CH2:6]2
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3C[C@H]4C[C@H]4N3)CC2)cc1
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC4CC4N3Cc3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 121.8 %

Procedure:
The title compound (D146) (67 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl methyl 4-(1-((3R)-2-azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoate (D104) (37 mg, 0.12 mmol) and 3-(Trifluoromethyl)benzyl bromide (0.029 ml, 0.19 mmol).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[C:11]1([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:11]1([N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:24]=2)[C:2]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCCCCCCCCCCCCOc1ccc(CNc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1ccc(CN(C(=O)c2cccnc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.8 %

Procedure:
To a room temperature slurry of 1.03 g of nicotinoyl chloride hydrochloride in 20 ml of methylene chloride is added, via cannula, 2.0 g of product from Example 145 in 30 ml of methylene chloride. After 5 minutes, 2.05 g of triethylamine is added and the reaction stirred at room temperature for 72 hours. The solution is poured into saturated sodium bicarbonate and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 40% ethyl acetate/hexane) to give 2.35 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[CH2:6][CH:7]=[CH:8][CH2:9][PH:10](=[O:12])[OH:11].I[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[CH2:6][CH:7]=[CH:8][CH2:9][PH:10](=[O:11])[O:12][CH2:20][CH3:21]
Reactant: CCI
Reactant: COc1cc(CC=CC[PH](=O)O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCO[PH](=O)CC=CCc1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (3-methoxy-4-nitrobenzyl)prop-2-en-1-ylphosphinic acid (Compound 37F, 1.28 g, 4.72 mmol) and iodoethane (1.47 g, 9.44 mmol) in DMF (5.0 mL) was charged with potassium carbonate (1.30 g, 9.44 mmol). The reaction mixture was allowed to stir at rt for 16 hours. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (25 mL). The organic layer was washed with water (10 mL), washed with brine (10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure to yield a yellow oil. The crude material was purified on a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→95:5) as eluent to afford the title compound as 1.08 g of a yellow oil (77%). 1H NMR (CDCl3, 400 MHz): δ=7.84 (d, J=8.3 Hz, 1H), 7.11 (t, J=1.8 Hz, 1H), 6.92 (td, J=1.8, 8.3 Hz, 1H), 5.76-5.90 (m, 1H), 5.18-5.32 (m, 2H), 4.00-4.14 (m, 2H), 3.98 (s, 3H), 3.19 (d, J=16.4 Hz, 2H), 2.60 (dd, J=7.3, 17.7 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H). MS (ESI): m/z 300.10 [M+H]+. UPLC: tR=1.22 min (UPLC-TOF: polar—3 min).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[S:17][CH:18]=[CH:19][C:20]=2[S:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:6]1[CH3:30].[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:31])=[O:2])[C:6]([CH3:30])=[C:7]2[CH2:15][C:16]1[S:17][CH:18]=[CH:19][C:20]=1[S:21]([C:24]1[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=1)(=[O:22])=[O:23]
Reactant: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccncc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2sccc2S(=O)(=O)c2ccncc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
A mixture of {5-fluoro-2-methyl-3-[3-(pyridine-4-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}acetic acid methyl ester (0.026 g) and tetrahydrofuran (0.5 mL) was treated with 2.0 M aqueous sodium hydroxide solution (2.0 mL), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was acidified by the addition of 2.0 M aqueous hydrochloric acid solution and concentrated under reduced pressure. The residue was purified by preparative HPLC, eluting with a mixture of acetonitrile and water (1:19 to 1:1 by volume) to afford the title compound as yellow solid (0.015 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12]>>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]2[O:10][C:11](=[O:12])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C)c(O)c(N)c1
Product: Cc1cc(C)c2oc(=O)[nH]c2c1

Procedure:
A mixture of 2-amino-4,6-dimethylphenol (412 mg, 3.00 mmol) and 1,1′-carbonyldiimidazole (730 mg, 4.50 mmol) in TIE (15 mL) was heated at reflux for 3 h. The mixture was allowed to cool, and the solvent removed under reduced pressure. The residue was taken up in EtOAc and washed with 1.0 N aqueous HCl (2×), then brine, then the EtOAc was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=164 (M+1).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[CH2:13](Br)[CH:14]=[CH2:15].[OH-].[Na+].C(OC(=O)C)C>CCCCCC>[CH2:15]([S:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=2[N:3]=1)[CH:14]=[CH2:13]
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCSc1nc2cc(C)c(C)cc2[nH]1
Yield: 93 %

Procedure:
2-Allylthio-5,6-dimethylbenzimidazole (III) was prepared as described above for I from 2,67 g (0,015 mol) 2-mercapto-5,6-dimethyl-benzimidazole, 2,1 g (0,017 mol) allylbromide in the presence 0,7 g (0,017 mol) sodium hydroxide, yield 2,5 g (76%), m.p. 119-120° C. (from mixture ethylacetate with hexane). 1H NMR (CDCl3), δ: 2,33 (6H, s, 2CH3); 3,89 (2H, d, CH2S); 5,10 (HB, d, CHC═CHAHB); 5,25 (HA,d, CHC═CHACHB); 7,30 (2H, broad s, ArH); 10,11 (1H, broad s, NH).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C)C=O.CCOCC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(COc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
27.6 g (0.2 mol) of 4-nitrophenol are dissolved in 300 ml of dimethylformamide and, after addition of 27.6 g (0.2 mol) of dried potassium carbonate, the mixture is stirred at room temperature for 45 minutes. Thereafter, 50.4 g (0.22 mol=34.9 ml) of benzyl bromoacetate are added dropwise, while stirring, and the suspension is then heated at 80° C. (oil bath temperature) for 5 hours. The oil bath is then switched off and the suspension is stirred for a further 15 hours, during which the reaction mixture slowly comes to room temperature. The undissolved inorganic salts are filtered off with suction and the mother liquor is concentrated to dryness in vacuo. The residue is dissolved in methylene chloride and, after washing twice with water, the solution is dried over sodium sulphate, filtered and concentrated. The product obtained is suspended in ether and filtered off with suction. Yield: 55.4 g (96.4% of theory).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([Cl:32])=[CH:27][CH:26]=2)=[O:22])=[O:7])(C)(C)C.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][C:38]2[N:41]=[C:42](C([O-])=O)[S:43][C:37]=2[CH2:36]1.[Li+]>C(O)C>[Cl:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:21]([NH:20][C@@H:10]1[CH2:11][CH2:12][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C@H:9]1[NH:8][C:6]([C:42]1[S:43][C:37]3[CH2:36][N:35]([CH3:34])[CH2:40][CH2:39][C:38]=3[N:41]=1)=[O:7])=[O:22])=[CH:31]2
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
(1R*,2R*,4S*)-N2-tert-Butoxycarbonyl-N1-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine was treated with a saturated ethanol solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]-pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.