Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2([NH2:13])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]([CH:33]3[CH2:35][CH2:34]3)[C:31](=[O:36])[N:30]([CH2:37][C:38](O)=[O:39])[N:29]=2)=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2([NH:13][C:38](=[O:39])[CH2:37][N:30]3[C:31](=[O:36])[N:32]([CH:33]4[CH2:34][CH2:35]4)[C:28]([C:25]4[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=4)=[N:29]3)[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: NC1(c2cccc(Cl)c2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)NC1(c2cccc(Cl)c2)CCC1
Reaction time: 0.17 h

Procedure:
57.2 mg (0.262 mmol) of 1-(3-chlorophenyl)cyclobutanamine hydrochloride are placed in 2 ml of dimethylformamide and treated with 26.5 mg (0.262 mmol) of triethylamine. After 10 mins' stirring, 70.0 mg (0.238 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 38.7 mg (0.286 mmol) of HOBt are added. After a further 10 mins' stirring, the mixture is treated with 59.4 mg (0.310 mmol) of EDC hydrochloride and stirred overnight at room temperature. For the workup, the reaction mixture is partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200:1, then 100:1) and thus yields 66 mg (61% of theory) of the target compound.
Reaction SMILES: [O:1]([CH:8]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:27](I)[CH3:28]>CN(C)C=O.C(OCC)(=O)C>[O:1]([C:8]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH2:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(OCC)C(Oc1ccccc1)P(=O)(OCC)OCC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(CC)(Oc1ccccc1)P(=O)(OCC)OCC
Reaction time: 0.75 h

Procedure:
Tetraethyl (phenoxymethylene)-bisphosphonate (1.14 g) was added to a suspension of 55% sodium hydride (0.15 g) in dimethylformamide (10 ml). After 45 minutes at room temperature, ethyl iodide (0.49 ml) was added, and the mixture was left overnight at room temperature, diluted with ethyl acetate and washed with 40% aqueous calcium chloride. The organic phase was dried and evaporated to leave an oil which was purified by chromatography on silica gel. The title compound was isolated as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:44]([N:47]1[C:51]2=[N:52][CH:53]=[C:54]([NH2:56])[CH:55]=[C:50]2[CH2:49][CH2:48]1)(=[O:46])[CH3:45]>CN(C=O)C>[C:44]([N:47]1[C:51]2=[N:52][CH:53]=[C:54]([NH:56][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:20])[CH:55]=[C:50]2[CH2:49][CH2:48]1)(=[O:46])[CH3:45]
Reactant: CC(=O)N1CCc2cc(N)cnc21
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc21
Temperature: 20 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
To a solution, stirred at 20° C., of 0.28 g (0.97 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid prepared in step 1.1, 186 mg (0.97 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and 131 mg (0.97 mmol) of 1-hydroxybenzotriazole (HOBT) in 15 mL of DMF are added 206 mg (1.17 mmol) of 1-acetyl-5-amino-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, prepared in step 1.2. The reaction mixture is stirred for 14 hours at 20° C. and then concentrated under reduced pressure. The resulting product is taken up in 100 mL of water. The suspension is then extracted with three times 30 mL of ethyl acetate. The combined organic phases are washed twice with 20 mL of water, dried over sodium sulfate and then concentrated under reduced pressure. The product obtained is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 290 mg of the expected product are thus isolated.
Reaction SMILES: [Mg].II.Br[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([Cl:13])[CH:7]=1.[F:14][C:15]([F:32])([F:31])[C:16](=[O:30])[CH2:17][C:18]([C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[O:28][CH3:29])([CH3:20])[CH3:19]>C(OCC)C>[Cl:12][C:10]1[CH:11]=[C:6]([CH2:5][C:16]([OH:30])([CH2:17][C:18]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])([CH3:20])[CH3:19])[C:15]([F:14])([F:32])[F:31])[CH:7]=[C:8]([Cl:13])[N:9]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: Clc1cc(CBr)cc(Cl)n1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc(Cl)nc(Cl)c1)C(F)(F)F

Procedure:
To a 100 mL dry round bottom flask was added 73 mg (3.0 mmol) of magnesium powder, a couple of I2 crystals, and 5 mL of dry diethyl ether, and the mixture was allowed to stir under argon. 4-Bromomethyl-2,6-dichloropyridine (723 mg, 3.0 mmol) in 10 mL of diethyl ether was added dropwise through a dropping funnel and the resulting mixture was heated to reflux for 1 hour. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (278 mg, 1.0 mmol) (Example 1) in diethyl ether (5 mL) was carefully added dropwise through a dropping funnel and the mixture was allowed to stir to reflux temperature for 4 hours and then overnight (16 hours) at room temperature. The reaction was quenched with the addition of 3 mL of aqueous NH4Cl solution, and the resulting mixture was extracted with three 30 mL portions of EtOAc, washed with H2O (10 mL) and brine (10 mL), and the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using an EtOAc-hexanes gradient. Combined product fractions were concentrated in vacuo to afford the desired product which was further purified by preparative-HPLC using a gradient of 80%-100% (CH3CN-water) in 15 minutes and a flow rate of 20 mL/min to afford 76 mg of the title compound (17.2% yield) as a yellowish liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[N:15]=[C:14]([NH:16][C:17]([NH:19][C:20]3[N:21]=[C:22]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[S:23][CH:24]=3)=[O:18])[CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:35](C)=O.[Na+]>C(Cl)Cl>[CH3:35][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[N:15]=[C:14]([NH:16][C:17]([NH:19][C:20]3[N:21]=[C:22]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[S:23][CH:24]=3)=[O:18])[CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1cccc(OCCC2CCNCC2)n1)Nc1csc(-c2ccncc2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC(CCOc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of N-[2-(4-pyridinyl)-4-thiazolyl]-N′-2-[6-(4-piperidinylethoxy)pyridinyl]urea (0.17 g, 0.40 mmol, Example 167), paraformaldehyde (0.17 g), and NaBH(OAc)3 (0.21 g, 1.0 mmol) in 40 mL of CH2Cl2 was stirred at RT under N2 for 12 h. After 12 h, the solvent was removed in vacuo, and the residue was diluted with 20 mL of H2O, then extracted with CHCl3/IpOH (3:1, 3×20 mL). The combined organic portions were washed with brine, and dried over MgSO4, and the solvents were removed in vacuo to yield a residue. Purification over silica gel (gradient, 5% to 7.5% MeOH/CH2Cl2 with 0.5% of TEA) provided the title compound as an off-white solid. MS m/z: 439 (M+H). Calc'd for C22H26N6O2S: 438.18.
Reaction SMILES: CN(C)CCCNC(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:45]=[C:46]([C:50]2[CH:55]=[CH:54][C:53]([C:56]([OH:58])=O)=[CH:52][CH:51]=2)[CH:47]=[CH:48][CH:49]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH2:65]>C1COCC1>[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:56]([C:53]1[CH:54]=[CH:55][C:50]([C:46]2[CH:47]=[CH:48][CH:49]=[C:44]([CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:45]=2)=[CH:51][CH:52]=1)=[O:58]
Reactant: O=C(O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1
Reactant: CN(C)CCCCN
Agent: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Solvent: C1CCOC1
Product: CN(C)CCCCNC(=O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (4-dimethylamino-butyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (1.50 g, 4.12 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.68 g, 4.20 mmol, 1.02 eq.) and 4-dimethylaminobutylamine (0.57 g, 4.94 mmol, 1.2 eq.). When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2c1
Yield: 44.8 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methoxyphenyl}-3-(1-cyano-1-methylethyl)benzamide (115 mg, 0.25 mmol), cyclopropanecarbonyl chloride (105 mg, 1.00 mmol), N,N-dimethylpyridine-4-amine (122 mg, 1.00 mmol) and pyridine (2 mL), and in the same manner as in Example A18(v), the title compound (59 mg, 45%) was obtained as a pale-yellow powder.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12](C(O)=O)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.ClC(OCC)=O.[NH2:31][C:32]1[C:41]([NH2:42])=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35].C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:31][C:32]1[C:41]([NH:42][C@H:12]2[CH2:13][CH2:14][C@@H:9]([NH2:8])[CH2:10][CH2:11]2)=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(N[C@H]2CC[C@@H](N)CC2)c1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.4 g (9.9 mmol) of cis-4-(tert-butoxycarbonylamino)-cyclohexanecarboxylic acid and 2.7 ml (19.7 mmol) of triethylamine were dissolved in 70 ml of anhydrous tetrahydrofuran and, at −10° C., a solution of 0.94 ml (9.9 mmol) of ethyl chloroformate in 25 ml of anhydrous tetrahydrofuran was added dropwise. The mixture was then stirred at 0° C. for 1 hour. After this, 1.6 g (9.9 mmol) of methyl 2,3-diaminobenzoate were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-water and made alkaline with aqueous sodium bicarbonate solution. This aqueous phase was extracted with ethyl acetate. The organic phase was then washed with aqueous sodium bicarbonate solution and water, dried and concentrated in vacuo. 2.7 g of the product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=3[CH:25]=2)=[CH:5][CH:4]=1.Cl>COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[S:18](=[O:19])(=[O:20])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=3[CH:25]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(OC)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Solvent: COCCOC
Product: COc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Yield: 86.3 %

Procedure:
To a solution of methyl 7-(4-methoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (463 mg) in 1,2-dimethoxyethane (30 ml) was added 6N hydrochloric acid (30 ml), and the mixture was refluxed for 18 hours and concentrated under reduced pressure to give crystals, which were collected by filtration. The crystals washed with 2-propanol and hexane to give pale yellow crystals of 7-(4-methoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (384 mg).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:17])[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:17])[CH2:6]1
Reactant: [N-]=[N+]=NCC1CCN(c2ccccc2)C(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCN(c2ccccc2)C(=O)C1
Reaction time: 1 h

Procedure:
4-(Azidomethyl)-1-phenylpiperidin-2-one (0.37 g, 1.3 mmol) was dissolved in tetrahydrofuran (10 mL) and treated with triphenylphosphine (0.36 g, 1.4 mmol, 1.05 equiv). After stirring for 1 hour, the mixture was treated with water (1 mL) and stirred for 14 hours. The mixture was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [ClH:1].[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH2:22])[S:19][CH:20]=1.[CH:23](=O)[CH2:24][CH2:25][CH2:26][CH3:27].C(=O)CC>>[ClH:1].[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[S:19][CH:20]=1
Reactant: NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Reactant: CCCCC=O
Agent: Cl
Solvent: CCC=O
Product: CCCCCNCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Yield: 38 %

Procedure:
The experimental protocol used is the same as that described for Stage 399.1 of Example 399, with the compound of Example 362 and valeraldehyde replacing intermediate 355.2 and propionaldehyde respectively. A dark-coloured solid is obtained with a yield of 38%. MH+=382.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C#N)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B9) (2.0 g, 7.11 mmol) and pyrrolidine (2.94 ml, 35.6 mmol) in DMSO (30 mL) at RT according to the general procedure C. Obtained as a yellow solid (1.97 g, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][CH2:11]O.S(Br)([Br:15])=O>C1(C)C=CC=CC=1>[Br:15][CH2:11][CH2:10][CH2:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: OCCCc1c(F)cccc1F
Reactant: O=S(Br)Br
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1CCCBr

Procedure:
6.86 g (39.8 mmol) of 3-(2,6-difluorophenyl)propan-1-ol (Example 1.2.4) is dissolved in 50 ml toluene and 19.1 g (92.0 mmol) of thionyl bromide is added. The mixture is refluxed for 3 hours, the solvent is eliminated and excess thionyl bromide is eliminated. Then the residue is purified by flash chromatography (cyclohexane). Yield: 6.98 g.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.Cl.[C:16](=[NH:21])(OCC)[CH3:17]>>[NH:21]=[C:16]([NH:10][NH:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:4][CH:5]=1)[CH3:17]
Reactant: CCOC(C)=N
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: CC(=N)NNC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
4.78 g (23.4 mmol) 4-(trifluoromethyl)benzoic acid hydrazide and 5.21 g (42.1 mmol) ethyl acetimidate hydrochloride are reacted as described for intermediate product 1a).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH3:22])[C:6]=2[C:5]([C:23](O)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH3:22])[C:6]=2[C:5]([C:23]([CH:27]([CH3:29])[CH3:28])=[C:24]([CH3:25])[CH3:26])=[CH:4][CH:3]=1
Reactant: COc1cc(Cl)cc(C)c1Nc1nc2c(Cl)ccc(C(O)(C(C)C)C(C)C)c2n1C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)cc(C)c1Nc1nc2c(Cl)ccc(C(=C(C)C)C(C)C)c2n1C
Yield: 78.9 %

Procedure:
A solution of 3-{4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl}-2,4-dimethylpentan-3-ol (75 mg, 0.17 mmol) in trifluoroacetic acid (3 mL) was heated at 70° C. for 1 h. After cooling, the reaction mixture was concentrated in vacuo, neutralized with saturated sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC eluting with a 5-95% acetonitrile/water gradient mixture to give the title compound (58 mg, 80%).
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:8]([CH2:9][NH:10]C(=O)C[Cl:13])=[C:7]([OH:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.Cl>[ClH:13].[NH2:10][CH2:9][C:8]1[CH:15]=[CH:16][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][C:7]=1[OH:17]
Reactant: CC(C)(C)c1ccc(CNC(=O)CCl)c(O)c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1ccc(CN)c(O)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
N-(4-tert-Butyl-2-hydroxybenzyl)-2-chloroacetamide (270.0 mg, 1.06 mmol) was dissolved in a mixture of EtOH (4.0 ml) and conc. HCl (1.3 ml). The mixture was stirred at 85° C. for 3.0 h. The solvents were removed under vacuum to afford 225 mg (98%) of the title compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[C:15][Si](C)(C)C)=[CH:11][CH:12]=2)[C@H:7]([NH:20][C:21](=[O:26])[O:22][CH:23]([CH3:25])[CH3:24])[CH2:6][C@@H:5]1[CH3:27])(=[O:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[CH3:25][CH:23]([O:22][C:21](=[O:26])[NH:20][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]#[CH:15])[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:27])[CH2:6]1)[CH3:24]
Reactant: CC(=O)N1c2ccc(C#C[Si](C)(C)C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reaction time: 0.58 h
Yield: 89 %

Procedure:
To a solution of 1-methylethyl {(2S,4R)-1-acetyl-2-methyl-6-[(trimethylsilyl)ethynyl]-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation, see Intermediate 59) (216 mg, 0.559 mmol) in tetrahydrofuran (THF) (3 mL) at room temperature was added TBAF (1M in THF, 0.671 mL, 0.671 mmol) and the resulting black mixture was stirred at this temperature for 35 min. Most of the solvent was removed in vacuo and the residue dissolved in AcOEt. The organic phase was washed with a saturated NaHCO3 aqueous solution then twice with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue on SP4 using a 10 G silica cartridge (Gradient: 13 to 63% AcOEt in Hexanes) gave 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (156 mg, 0.496 mmol, 89% yield) as a very pale yellow foam.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:17])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[S:11][CH:12]=1)[CH3:2].[OH-].[Na+]>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:17])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[S:11][CH:12]=1)[CH3:2]
Reactant: CCc1cnn(C)c1-c1csc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cnn(C)c1-c1csc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (192 mg, 0.77 mmol) in Tetrahydrofuran (THF) (4 mL). 6N NaOH (4 mL, 24.0 mmol) was added slowly, the reaction stirred at 70° C. overnight. The reaction was cooled to room temperature, partitioned between CHCl3 and H2O and the pH of the aqueous layer adjusted to pH 3 by the addition of 6N HCl. The layers were separated, the organic layer dried with Na2SO4 and solvent removed affording the title compound (181 mg, quant.) used without further purification: LC-MS (ES) m/z=237 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=2[C:10]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([C:17]([N:19]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22](=[S:30])[CH2:21][CH2:20]3)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:38][N:39]([CH3:44])[CH2:40][CH2:41][CH2:42]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH3:38][N:39]([CH3:44])[CH2:40][CH2:41][CH2:42][S:30][C:22]1[CH2:21][CH2:20][N:19]([C:17](=[O:18])[C:16]2[CH:31]=[CH:32][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:33]=[CH:34][CH:35]=[CH:36][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:14][CH:15]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1
Reactant: CN(C)CCCCl
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=S)Nc4ccccc43)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(SCCCN(C)C)=Nc4ccccc43)cc2)cc1
Yield: 37.1 %

Procedure:
A solution of 5-(4-[2-(4-methylphenyl)benzoylamino]-benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepine-2(2H)thione (460 mg), 3-dimethylaminopropyl chloride hydrochloride (740 mg), potassium carbonate (1.29 g) and sodium iodide (catalytic amount) in acetone (40 ml) was stirred for 19 hours at 60° C. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography (SiO2 30 g, 5% methanol in chloroform) to give 2-[3-(dimethylamino)propylthio]-5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-4,5-dihydro-3H-1,5benzodiazepine (200 mg).