Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@H:8]2[CH2:9][C@@H:3]1[CH2:4][CH2:5][C:6]2=[CH2:7].B1C2CCCC1CCC2.C([O-])(C)(C)C.[K+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>C1COCC1.CCCCC>[CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:7][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]
Reactant: C=C1CC[C@H]2C[C@@H]1C2(C)C
Reactant: O=C(CBr)c1ccccc1
Agent: B1C2CCCC1CCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC1(C)C2CCC(CCC(=O)c3ccccc3)C1C2
Temperature: -78 °C
Reaction time: 3 h
Yield: 5.5 %

Procedure:
1.36 g (−)-β-pinene (10 mmol) was dissolved in 5 ml THF. 21 ml of a 0.5-molar solution of 9-BBN in THF (10.5 mmol) was added to this solution at 0° C. The reaction mixture was slowly brought to room temperature and stirred for a further 3 hours. The resulting solution was cooled to −78° C., and a solution of 1.12 g potassium tert-butanolate (10 mmol) in 10 ml THF was then added to the cooled reaction solution. After a short time, 2 g α-bromacetophenone (10 mmol) was added in portions with constant stirring. The reaction mixture was slowly brought to room temperature and stirred for 4 hours at room temperature. The resulting product mixture had 50 ml n-pentane added to it, and washed three times in each case with 10 ml of a 3N sodium hydroxide solution and with 10 ml water. The organic phase was dried over magnesium sulfate. Solvent was removed from the filtrate at reduced pressure. The raw product was purified by column chromatography. 140 mg (10%) of the aforesaid product was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C@@H:10]([NH2:14])[CH2:11]2)=[CH:6][CH:5]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:14][C@@H:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[CH2:11]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: COc1ccc2c(c1)C[C@H](N)CC2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc2c(c1)C[C@H](NC1CCN(C(=O)OC(C)(C)C)CC1)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
To a solution of (R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride (6.0g, 28.1 mmol)(prepared as described in the French patent FR 2,653,765 or available commercially) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (6.7g, 33.7 mmol, 1.2 eq.) in dichloroethane (200 mL) under an inert atmosphere was added sodium triacetoxyborohydride (14.9 g, 70.2 mmol, 2.5 eq). The reaction was stirred at room temperature for 24 h then concentrated in vacuo. The residue was partitioned between EtOAc (200 mL) and 5% KOH (150 mL). The aqueous layer was extracted twice more with EtOAc (2×75 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford 4-((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (9.7 g).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[BrH:5].[Br:6][CH:7]1[C:12](=O)[CH2:11][CH2:10][NH:9][CH2:8]1>C(O)C>[BrH:6].[BrH:5].[N:1]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[S:3][C:2]=1[NH2:4]
Reactant: O=C1CCNCC1Br
Reactant: NC(N)=S
Agent: Br
Solvent: CCO
Product: Nc1nc2c(s1)CNCC2
Yield: 84.9 %

Procedure:
4.55 g thiourea was added to 15.2 g 3-Bromo-piperidin-4-one hydrobromide in 152 mL ethanol and refluxed for 20 h. The reaction was cooled and the solid was filtered, washed with ethanol and dried to give 15.8 g of the desired product., (M+H)+: 184
Reaction SMILES: C(OC(=O)NC(C)(C)C/C=C/[C:12](=O)[N:13]([C@@H:15]([C:27](=[O:48])[N:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH3:29])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:42]1([S:39]([NH:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH2:31][CH2:30][N:28]([CH3:29])[C:27](=[O:48])[C@H:15]([NH:13][CH3:12])[CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)(=[O:41])=[O:40])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CN(CCc1ccccc1NS(=O)(=O)c1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 111.6 %

Procedure:
A solution of {(3E)-4-[N-((1R)-1-{N-[2-(2-(phenylsulfonylamino)phenyl)ethyl]-N-methylcarbamoyl}2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl}carbamic acid tert-butyl ester (330 mg, 0.45 mmol) in dichloromethane (3 ml) was cooled to 0° C. Trifluoroacetic acid (3 ml) was added. The reaction mixture was stirred for 40 min at 0° C. It was diluted with dichloromethane (20 ml). A saturated aqueous solution of sodium hydrogen carbonate (6 ml) was added. Solid sodium hydrogen carbonate was added until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×20 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (20 g), using dichloromethane/methanol/25% aqueous ammonia 100:10:1 as eluent, to give 252 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:43]1([S:48](Cl)(=O)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44]1.O>C(Cl)Cl.N1C=CC=CC=1>[CH:43]1([S:48]([NH:1][C:2]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:3]=2[O:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2N)cc1
Reactant: O=S(=O)(Cl)C1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2NS(=O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.9 %

Procedure:
To a solution of methyl 4-(2-amino-5-trifluoromethylphenoxymethyl)benzoate (300 mg) in methylene chloride (3.0 ml), pyridine (187 μml) and triphenylphosphine (315 mg) were added in a stream of argon. At 0° C., cyclopentylsulfonylchloride (202 mg) was added dropwise thereto. The mixture was stirred for 6 hours at room temperature. To the reaction mixture, water was added. The mixture was extracted with ethyl acetate, washed, dried over and concentrated with the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=2:1→1:1) to give the title compound (309 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31]Cl)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CCC(=O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17](=[O:25])[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:31][CH2:30][CH2:29][N:28]([CH2:33][CH3:34])[CH2:26][CH3:27])=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccc(Cl)cc1
Reactant: CCN(CC)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: CCN(CC)CCCOc1ccc(C(=O)c2oc3ccccc3c2-c2ccc(Cl)cc2)cc1

Procedure:
(0.009 mol.) of 3-(4-chlorophenyl)-2-(4-hydroxybenzoyl)benzofuran with 1.4 g. (0.009 mol.) of 3-diethylaminopropyl chloride in 50 ml. of dry 3-pentanone containing 5.2 g. (0.04 mol.) of potassium carbonate by the method described in Example 1 gives the title compound.
Reaction SMILES: O[CH2:2][CH:3]=C(CCC=C(CCC=C(C)C)C)C.CC(C)=CCC/C(/C)=C/CC/C(/C)=C/C=O.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[CH3:46][CH:47]([CH2:54][CH2:55][CH2:56][CH:57]([CH3:64])[CH2:58][CH2:59][CH2:60][CH:61]([CH3:63])[CH3:62])[CH2:48][CH2:49][CH2:50][C:51](=[O:53])[CH3:52].[C-]#[C-]>CC(C)=O>[CH3:62][CH:61]([CH2:60][CH2:59][CH2:58][CH:57]([CH2:56][CH2:55][CH2:54][CH:47]([CH2:48][CH2:49][CH2:50][C:51]([OH:53])([CH:2]=[CH2:3])[CH3:52])[CH3:46])[CH3:64])[CH3:63]
Reactant: CC(=O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Product: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C

Procedure:
A particularly preferred embodiment of synthesizing vitamin E from farnesol is illustrated in FIG. 3. Farnesol 3-8 is oxidized to farnesal 3-9 under Oppenauer oxidation conditionS using aluminum isopropoxide and acetone. Farnesal 3-9 is then converted to dehydrofarnesyl acetone 3-10 by an aldol condensation reaction with acetone. Reduction of olefin moieties on dehydrofarnesyl acetone 3-10 by hydrogenation then produces 6,10,14-trimethyl pentadecan-2-one 3-11. Addition of acetylide to the ketone 3-11 then generates propargylic alcohol 3-12 which is partially reduced using Lindlar hydrogenation condition to produce isophytol 3-13. Reaction of isophytol 3-13 with 2,3,5-trimethyl hydroquinone 3-5 in the presence of an acid catalyst then produces vitamin E.
Reaction SMILES: [CH3:1][CH:2](C)[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5].BrCC1C=CC(C2C=CC([N+]([O-])=O)=CC=2)=CC=1C(OC)=O.Cl.NC1(C(OC)=O)CC1>>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][N:8]([C:3]4([C:4]([O:6][CH3:7])=[O:5])[CH2:2][CH2:1]4)[C:9]3=[O:26])=[CH:14][CH:13]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Agent: COC(=O)C1(N)CC1
Agent: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1CBr
Agent: Cl
Product: COC(=O)C1(N2Cc3ccc(-c4ccc([N+](=O)[O-])cc4)cc3C2=O)CC1
Yield: 65 %

Procedure:
The compound of example 583 was prepared analogous to compound of example 5 by reaction of compound of example 4 with methyl 1-aminocyclopropanecarboxylate hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:19])[C:7](=[O:18])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.N[C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[O:30][CH2:31][CH3:32].O.Cl>C(O)C>[CH:13]1([N:10]2[CH2:9][CH2:8][C:7](=[O:18])[N:6]([CH3:19])[C:5]3[C:11]2=[N:12][C:2]([NH:1][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[O:30][CH2:31][CH3:32])=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(N)ncc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Yield: 44.7 %

Procedure:
To a solution of 10-Chloro-2-cyclopentyl-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1; 280 mg, 1 mmol) and 4-amino-3-ethoxybenzoic acid (WO 2001077101; 205 mg, 1.13 mmol) in ethanol (5 mL) was added water (15 mL) and conc hydrochloric acid (0.17 mL, 2 mmol). The mixture was heated under reflux for 36 hours. The reaction was cooled and a brown solid precipitated. This was filtered and dried, triturated under cold acetonitrile and then dried in vacuo. To yield the title compound as a brown solid (190 mg; 45%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:22])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: COc1nc2c(cc1NC(=O)Oc1ccccc1)CCCC2
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2c(cc1NC(=O)N1CCN(c3cc(C)cc(C)c3)CC1)CCCC2
Yield: 51 %

Procedure:
Phenyl N-(2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C(F)(F)F)cc2)CC1
Yield: 47 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (47%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Product: Nc1cc([N+](=O)[O-])ccc1C(=O)Cl
Temperature: 25 °C
Yield: 119.8 %

Procedure:
2-Amino-4-nitrobenzoic acid (15 g, 82 mmol) was refluxed with sulfurous dichloride (40 mL, 82 mmol) for 2.5 hours. The reaction mixture was cooled to room temperature and concentrated to give Intermediate 69A (19.7 g, 119%) as a brown oil. HPLC: Rt=2.323 (as methyl ester) min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm.). MS (ES): m/z=197 (as methyl ester) [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([CH2:25][NH2:26])=[N:3]1.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=2)=[N:5][C:4]([CH2:25][NH:26][C:34]([NH:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])=[N:3]1
Reactant: Cn1nc(CN)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Product: Cn1nc(CNC(=O)Nc2ccccc2)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 3 h

Procedure:
A mixture of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanamine (0.75 g) and phenyl isocyanate (0.25 ml) in dry acetonitrile was stirred at 30° for 3 h. The solvent was removed in vacuo and the solid residue was crystallized from methyl acetate and petroleum ether (b.p. 60°-80°) to give the title compound (0.94 g) as a white solid, m.p. 120°-1°. T.l.c. System A, Rf 0.6.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:20][N:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>Cl>[NH:20]1[C:16]([C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=2)=[CH:17][CH:18]=[N:19]1
Reactant: CC(=O)N1CCN(c2ccc(-c3ccn[nH]3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1cc(-c2ccc(N3CCNCC3)cc2)[nH]n1
Yield: 99.8 %

Procedure:
To 5.1 g of 1-acetyl-4-(4-1H-pyrazol-5-ylphenyl)-piperazine, 60 ml of concentrated hydrochloric acid were added, followed by heating at reflux for 3 hours. After the completion of the reaction, the reaction solution was cooled and then neutralized with an aqueous 1N sodium hydroxide solution, thereby to precipitate a crystal. The resulting crystal was filtered, washed with a small amount of water and then dried to obtain 4.3 g of the objective 1-(4-1H-pyrazol-5-ylphenyl)-piperazine (melting point: 290° C. or higher).
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[CH:5]=[C:4]([O:16][CH3:17])[C:3]=1[F:18].[Br:19]N1C(=O)CCC1=O>>[Br:19][C:5]1[C:6]2[C:7]3[CH:15]=[CH:14][S:13][C:8]=3[C:9](=[O:12])[NH:10][C:11]=2[C:2]([F:1])=[C:3]([F:18])[C:4]=1[O:16][CH3:17]
Reactant: COc1cc2c([nH]c(=O)c3sccc32)c(F)c1F
Reactant: O=C1CCC(=O)N1Br
Product: COc1c(F)c(F)c2[nH]c(=O)c3sccc3c2c1Br
Yield: 52.5 %

Procedure:
Following Step 4 from General Procedure A, 6,7-difluoro-8-methoxythieno[2,3-c]quinolin-4(5H)-one (300 mg, 1.1 mmol) was reacted with N-bromosuccinimide (400 mg, 2.2 mmol) to afford the desired product (200 mg, 57%) as a yellow solid: ESI MS m/z 347 [C12H6BrF2NO2S+H]+.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[CH2:8]([C@H:15]([C:42]([NH:44][C@H:45]1[CH2:51][CH2:50][S:49][C@H:48]2[CH2:52][CH2:53][CH2:54][C@@H:55]([C:56]([O:58][CH3:59])=[O:57])[N:47]2[C:46]1=[O:60])=[O:43])[CH2:16][CH2:17][C@@H:18]([C:23](=[O:41])[NH:24][C@H:25]1[CH2:31][CH2:30][S:29][C@H:28]2[CH2:32][CH2:33][CH2:34][C@@H:35]([C:36]([O:38][CH3:39])=[O:37])[N:27]2[C:26]1=[O:40])[CH2:19][C:20]([OH:22])=[O:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.CO>[CH2:8]([C@H:15]([C:42]([NH:44][C@H:45]1[CH2:51][CH2:50][S:49][C@H:48]2[CH2:52][CH2:53][CH2:54][C@@H:55]([C:56]([O:58][CH3:59])=[O:57])[N:47]2[C:46]1=[O:60])=[O:43])[CH2:16][CH2:17][C@H:18]([CH2:19][C:20]([O:22][CH3:2])=[O:21])[C:23]([NH:24][C@H:25]1[CH2:31][CH2:30][S:29][C@H:28]2[CH2:32][CH2:33][CH2:34][C@@H:35]([C:36]([O:38][CH3:39])=[O:37])[N:27]2[C:26]1=[O:40])=[O:41])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)CC(=O)O)C(=O)N21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C[C@@H](CC[C@H](Cc1ccccc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
TMS-diazomethane (2.0 M in ether, 0.0061 mL, 0.012 mmol) was added to a solution of (3R,6R)-6-benzyl-7-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylamino)-3-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamoyl)-7-oxoheptanoic acid (5.4 mg, 7.0 mmol) in DCM (0.06 mL) and MeOH (0.0062 mL). Gas evolution occurred. The reaction was stirred at rt for 1 hr. The reaction mixture was concentrated and triturated with hexanes. The solid was dried over vacuum to give methyl (4S,7S,10aS)-4-(((2R,5R)-5-benzyl-6-(((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepin-4-yl)amino)-2-(2-methoxy-2-oxoethyl)-6-oxohexanoyl)amino)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (5.0 mg, 0.0063 mmol, 91% yield) as a white solid. Anal. Calcd. for C38H52N4O10S2 m/z 788.7. found: 789.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (1H, d), 7.25-7.21 (2H, m), 7.19-7.11 (3H, m), 7.00 (1H, d), 5.39 (1H, t, J=4.7 Hz), 5.36 (1H, t, J=4.7 Hz), 5.21-5.16 (1H, m), 5.16-5.12 (1H, m), 5.10-4.98 (2H, m), 3.72 (3H, s), 3.69 (3H, s), 3.65 (3H, s), 3.28-3.10 (2H, m), 2.98-2.81 (3H, m), 2.77-2.62 (3H, m), 2.47-2.37 (3H, m), 2.34 (1H, dd, J=15.7, 3.6 Hz), 2.27-2.19 (1H, m), 2.08-1.95 (4H, m), 1.88 (1H, ddd, J=10.9, 7.0, 3.6 Hz), 1.76-1.47 (12H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[C:13]3=[C:23]([CH3:26])[CH:24]=[CH:25][N:12]3[N:11]=2)[C:3]=1Br.[F:28][CH:29]([F:46])[C:30]1[CH:31]=[C:32]([OH:45])[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[C:13]3=[C:23]([CH3:26])[CH:24]=[CH:25][N:12]3[N:11]=2)[C:3]=1[C:34]1[CH:33]=[C:32]([OH:45])[CH:31]=[C:30]([CH:29]([F:46])[F:28])[CH:35]=1
Reactant: CC1(C)OB(c2cc(O)cc(C(F)F)c2)OC1(C)C
Reactant: Cc1ccn2nc(CNc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc(CNc3ncnc(N)c3-c3cc(O)cc(C(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 90 °C
Reaction time: 18 h
Yield: 43.4 %

Procedure:
To a solution of 2-(((6-amino-5-bromopyrimidin-4-yl)amino)methyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.16 mmol) in dioxane (2 ml) were added 3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (67 mg, 0.25 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (13 mg, 0.02 mmol) and 246 μl of a 2M aqueous solution of cesium carbonate. The mixture was stirred under argon atmosphere at 90° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to obtain 34 mg (42% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[C:19]([O:24][CH3:25])(=[O:23])[C:20](C)=[CH2:21]>CO>[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][CH2:21][CH2:20][C:19]([O:24][CH3:25])=[O:23])[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: C=C(C)C(=O)OC
Reactant: Cc1c(O[C@H]2CC[C@H](N)CC2)ccc2[nH]ncc12
Solvent: CO
Product: COC(=O)CCN[C@H]1CC[C@H](Oc2ccc3[nH]ncc3c2C)CC1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of the trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine (98.1 mg, 0.40 mmol) obtained in Example 408, methyl methacrylate (43 mg, 0.50 mmol) and methanol (2.0 ml) was stirred at 50° C. for 6 hours. The solvent was distilled off and the residue oil was subjected to elution by a silica gel column chromatography (ethyl acetate→ethyl acetate/triethylamine=20:1) to obtain methyl 3-({trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-amino}propanoate (121 mg, 91%).
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([OH:12])=O)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>O1CCCC1>[F:13][CH:2]([F:1])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(C(F)F)[nH]c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1ccc(C(F)F)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolution of 200 mg (1.1 mmol) of 6-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid in 25 ml of tetrahydrofuran and addition of 206 mg (1.3 mmol) of N,N-carbonyldiimidazole, the mixture was stirred initially at room temperature for 30 min and then under reflux for 30 min. A solution of 66 mg (1.1 mmol) of isopropylamine in 5 ml of tetrahydrofuran was then added dropwise, and the mixture was heated under reflux for a further 2 h. The solution was evaporated to dryness, the residue was then taken up in ethyl acetate and the mixture was washed with 2N hydrochloric acid and water, dried and concentrated. Purification by column chromatography gave 150 mg (61% of theory) of a colorless powder.