Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([Cl:14])[CH:10]=[C:11]([CH2:13][Br:15])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCCc1cc(C)cc(Cl)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCCc1cc(Cl)cc(CBr)c1

Procedure:
A mixture of 3-chloro-5-methylphenylethyl acetate (0.20 g; 0.958 mol), N-bromosuccinimide (0.21 g; 1.21 mmol) and 2,2-azobis(isobutyronitrile) (0.01 g; 0.037 mmol) in carbon tetrachloride (2 ml) were refluxed for 2 hours. After cooling and filtration of the precipitate, the filtrate was condensed under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=20:1) to give 3-bromomethyl-5-chlorophenylethyl acetate as colorless oil (0.16 g; 57%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[C:6](=[N+]=[N-])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH:2]=[CH2:3]>ClCCl.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[F:14][C:9]1[CH:8]=[C:7]([C:6]23[CH2:3][CH:2]2[CH2:1][O:4][C:5]3=[O:17])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: C=CCOC(=O)C(=[N+]=[N-])c1ccc(F)c(F)c1
Agent: [Rh]
Solvent: CCCCCCCC(=O)O
Solvent: ClCCl
Product: O=C1OCC2CC12c1ccc(F)c(F)c1
Yield: 72.9 %

Procedure:
Diazo-(3,4-Difluoro-phenyl)acetic acid allyl ester (70 g) was dissolved in dichloromethane (1000 mL) and added slowly during 36 h via a syringe pump (alternatively it is added dropwise via an addition funnel; 30 mL pr. hour) to a refluxing solution of rhodium (II) octanoate dimer (1.17 g, 1.5 mmol) in dichloromethane (200 mL). After all diazo compound has been added, the mixture is refluxed for another 30 min, then was evaporated in vacuo and crystallised by addition of cyclohexane (200 mL). This gave 30 g crystalline. Further 15 g was isolated from the motherliq. by repeated evaporation and crystallisation giving in total 45 g 1-(3,4-Difluoro-phenyl)-3-oxa-bicyclo[3.1.0]hexan-2-one.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH3:8].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-]>C(Cl)Cl>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]([NH2:9])[CH2:7][CH3:8]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1nnco1
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)c1nnco1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 72 %

Procedure:
tert-butyl N-[(1R)-1-(1,3,4-oxadiazol-2-yl)propyl]carbamate (2.255 g, 9.923 mmol) was dissolved in DCM (17.76 mL) at 0° C. and TFA (17.76 mL) was added. The reaction was stirred at 0° C. for 4.5 hours then concentrated under high vacuum. The residue was azeotroped with DCM (×2). The resultant oil was dissolved in a mixture of THF (40 ml) and DCM (20 ml) then treated with MP-carbonate (15 g, 199.9 mmol). The reaction was stirred gently for 1 hour then filtered. The resin was stirred with further portions DCM (2×25 ml) and filtered. The combined filtrates were filtered and concentrated to give the sub-title compound as a colourless oil (908 mg, 72%); 1H NMR (400.0 MHz, DMSO) d 0.86 (3H, t), 1.61-1.80 (2H, m), 2.23 (2H, br hump), 3.98 (1H, m), 9.15 (1H, s); MS ES (+) 128.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[N:14]=[C:15](S(C)(=O)=O)[N:16]=[CH:17][C:12]=2[S:11][C:10]=1[C:22]([O:24][CH3:25])=[O:23].[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][CH:40]=[O:41])=[C:35]([O:42][CH:43]([CH3:45])[CH3:44])[CH:34]=2)[CH2:29][CH2:28]1.CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C>CN(C=O)C>[CH:40]([N:39]([C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]2)=[CH:34][C:35]=1[O:42][CH:43]([CH3:45])[CH3:44])[C:15]1[N:16]=[CH:17][C:12]2[S:11][C:10]([C:22]([O:24][CH3:25])=[O:23])=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[C:13]=2[N:14]=1)=[O:41]
Reactant: CC(C)Oc1cc(N2CCN(C)CC2)ccc1NC=O
Reactant: COC(=O)c1sc2cnc(S(C)(=O)=O)nc2c1-c1ccccc1OC
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1sc2cnc(N(C=O)c3ccc(N4CCN(C)CC4)cc3OC(C)C)nc2c1-c1ccccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
A mixture of 1.80 g of methyl 7-(2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate, 1.37 g of N-[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide and 4.44 g of 1-[N-(2-methylpropan-2-yl)-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]pyrrolidine (BTPP) in 50 ml of anhydrous DMF is stirred at ambient temperature for 16 h. The mixture is then evaporated under vacuum at a temperature of 55° C., and the residue is diluted with ethyl acetate and water. The aqueous phase is extracted three times with ethyl acetate. The organic phases are washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product is purified on 100 g of silica, elution being carried out with 0-2.5% of methanol containing 10% by volume of 28% aqueous ammonia solution in dichloromethane, so as to obtain 2.264 g of methyl 2-{formyl[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxylate in the form of a brown solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]2([NH2:29])[CH2:28][CH2:27][CH2:26]2)[N:21]=1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:29][C:25]3([C:22]4[N:21]=[C:20]([CH3:19])[O:24][N:23]=4)[CH2:28][CH2:27][CH2:26]3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc(C2(N)CCC2)no1
Agent: Cl
Product: Cc1nc(C2(NC(=O)c3ccc(C4CC4)c(OCC4CC4)n3)CCC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 1-(5-methyl-1,2,4-oxadiazol-3-yl)-cyclobutanamine hydrochloride (1:1) (CAN 1170897-28-5) as starting materials, LC-MS (UV peak area/ESI) 97.8%, 369.1914 (M+H)+.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][NH2:9].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2O[C:26]([C:29]34[CH2:36][CH2:35][C:32]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([CH2:33][CH2:34]3)[CH2:31][CH2:30]4)=[N:27][N:28]=2)=[C:20]([C:43]([F:46])([F:45])[F:44])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:9]([CH3:8])[C:26]([C:29]34[CH2:36][CH2:35][C:32]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([CH2:31][CH2:30]3)[CH2:33][CH2:34]4)=[N:27][N:28]=2)=[C:20]([C:43]([F:44])([F:45])[F:46])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: FC(F)(F)c1cc(OCc2ccccc2)ccc1-c1nnc(C23CCC(c4ccccc4)(CC2)CC3)o1
Reactant: CN
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: Cn1c(-c2ccc(OCc3ccccc3)cc2C(F)(F)F)nnc1C12CCC(c3ccccc3)(CC1)CC2
Temperature: 150 °C

Procedure:
The trifluoroacetate salt of methylamine (380 mg, 2.61 mmol) and 2-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole (8-D) were suspended in a 2 M solution of methylamine in methanol (1.3 mL, 2.61 mmol) and heated at 150° C. overnight. After being cooled to room temperature, the reaction mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate (30 mL). The layers were separated and the aqueous layer extracted with twice with ethyl acetate (25 mL). The combined organic layers were washed with brine, dried (MgSO4), and solvent removed in vacuo. The residue was then dissolved in methanol (8 mL) and purified by reverse phase chromatography using gradient elution with 10% acetonitrile (0.1% TFA) /water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 10 min (20 mL/min). The fractions containing product were partitioned between saturated aqueous sodium bicarbonate (25 mL) and methylene chloride (15 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (15 mL) three times, dried (MgSO4), and the solvent removed in vacuo to afford 3-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]-4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (8-E). MS: m/z 518 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH:32]([NH2:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:32]([NH:45][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:31])([F:29])[F:30])[C:9]=3[CH:17]=2)=[CH:26][CH:25]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NC(c1ccccc1)c1ccccc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with benzhydrylamine as in General Procedure 10 to give the title compound. LCMS: m/z=613.00 (M+H+); retention time=1.06 minutes.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([CH3:37])[C:19]([C:21]3[C:29]4[C:24](=[C:25]([C:30](=[O:36])[N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[BH4-].[Na+].CO>C(#N)C.CC(O)C>[CH2:34]([N:31]([CH2:32][CH3:33])[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[NH:23][CH:22]=[C:21]2[CH2:19][C@H:18]([NH2:17])[CH3:37])=[O:36])[CH3:35]
Reactant: CCN(CC)C(=O)c1cccc2c(C(=O)[C@@H](C)NC(=O)OCC3c4ccccc4-c4ccccc43)c[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)O
Solvent: CO
Product: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)N)c[nH]c12
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A solution of (R)-[2-(7-diethylcarbamoyl-1H-indol-3-yl)-1-methyl-2-oxoethyl]carbamic acid 9H-fluoren-9-ylmethyl ester (10.24 g, 20.1 mmol) in a mixture of acetonitrile (134 mL) and 2-propanol (7.7 ml) is added sodium borohydride (3.80 g, 100 mmol) in portions at room temperature with stirring, and the mixture is refluxed for 4 hours. The reaction solution is cooled to room temperature, and thereto is added dropwise methanol (200 ml). The reaction mixture is concentrated to dryness under reduced pressure. To the residue are added ethyl acetate and water, and the mixture is stirred. The organic layer is separated, washed with a saturated brine, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (methanol/(a saturated ammonia solution in chloroform)=1/100) to give the desired (R)-3-(2-aminopropyl)-1H-indole-7-carboxylic acid diethylamide (3.60 g, yield: 66%).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=O>O1CCCC1>[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:11]\[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=CCCCCCCCBr
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCC/C=C\CCCCCCCBr

Procedure:
48.5 g (0.1 mol) of (7-carboxyheptyl)triphenylphosphonium bromide were suspended in 150 ml of tetrahydrofuran. After the addition of 24.7 g (0.22 mol) of potassium t-butylate in 50 ml of tetrahydrofuran 26.4 g (0.12 mol) of 8-bromooctanal were added dropwise. After the usual work up 35.4 g of crude 8Z-16-bromohexadec-8-enoic acid were obtained having the following characteristics: Z/E=93/6;
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH:7]([OH:9])[CH3:8])[N:4]([CH3:10])[N:3]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:1][C:2]1[N:6]=[C:5]([C:7](=[O:9])[CH3:8])[N:4]([CH3:10])[N:3]=1
Reactant: CC(O)c1nc(Br)nn1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1nc(Br)nn1C
Temperature: 0 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
A solution of 1-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)ethanol (1.639 g, 7.95 mmol, Eq: 1.00) and pyridine (944 mg, 965 μl, 11.9 mmol, Eq: 1.5) in dichloromethane (237 ml) was cooled to 0° C. then Dess-Martin periodinane (15% in dichloromethane, 24.7 g, 8.75 mmol, Eq: 1.1) was added. The resulting mixture was stirred for 4 hours at 0° C. under nitrogen atmosphere. The mixture was diluted with dichloromethane and washed with sat. sodium hydrogen carbonate. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using dichloromethane/methanol 0-3% & 5% NH3 as eluent affording 1-(5-bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-ethanone (948 mg, 58.4%) as a white solid. MS: m/z=203 (EI)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH2:23][NH2:24]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:20]([CH3:19])[CH:21]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Reactant: Cc1ccc(CN)cc1C
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(-c3ccccn3)c2C#N)cc1C

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile and 3,4-dimethylbenzylamine in DME. ES-MS m/e (%): 331 (M+H+, 100).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15][CH:14]3[O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]4[O:39][CH2:38][CH2:37][N:36]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:35]=4[CH:45]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CO.[OH-].[K+]>O1CCOCC1.O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH:14]3[O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]4[O:39][CH2:38][CH2:37][N:36]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:35]=4[CH:45]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(Cn4ccnc4)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COCCCN1CCOc2ccc(COC3CNCCC3c3ccc(Cn4ccnc4)cc3)cc21
Temperature: 100 °C
Reaction time: 5 h

Procedure:
0.0978 g of benzyl 4-(4-imidazol-1-ylmethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate is dissolved in 3 ml of dioxane. 3 ml each of methanol and 40% KOH are added and the reaction mixture is stirred in a sealed flask at 100° C. over 5 hours. The reaction mixture is subsequently cooled to room temperature, diluted with 10 ml of water and extracted with ethyl acetate (3×30 ml). The combined organic phases are washed with 10 ml of water, then 10 ml of brine, dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: O=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C@@H:21]([N:23]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:22])=[O:18])[CH2:13][CH2:12]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>C1(C)C=CC=CC=1>[S:47]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C@@H:21]([N:23]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:22])=[O:18])[CH2:13][CH2:12]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@@H](COC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1)N(Cc1ccccc1)Cc1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H](COC(=O)N1CCC(n2c(=S)[nH]c3ccccc32)CC1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
To a solution of 147 mg (0.295 mmol, 1 equiv.) (S)-2-(dibenzylamino)propyl 4-(1,2-dihydro-2-oxobenzo[d]imidazol-3-yl)piperidine-1-carboxylate in 3 ml of toluene was added 89 mg (0.221 mmol, 0.221 equiv.) of Lawesson reagent. The suspension was refluxed overnight. The solid was filtered and the solvent evaporated in vacuum. The residue was purified on silica gel.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-])=O)=[CH:13][CH:14]=2)[CH2:9]1)=[O:5])[CH3:2]>C(O)C.[H][H].[C].[Pd]>[NH2:18][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH2:17][N:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:9]2)=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: CCOC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCN1CCc2ccc(N)cc2C1
Yield: 89.7 %

Procedure:
1.1 g of 2-(2-(ethoxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 20 ml of ethanol, and a catalytic amount of 10% palladium-carbon was added to the solution. The solution was stirred overnight in hydrogen atmosphere. The catalyst was separated by filtration and the solvent was distilled off under reduced pressure to obtain 0.88 g of 7-amino-2-(2-(ethoxycarbonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline, which was an oily product. This product with no further purification was dissolved in 10 ml of DMF, and 1.3 g of 1-(benzyloxycarbonyl)-4-(carboxymethoxy)piperidine and 1.1 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide which have been separately synthesized were added to the solution. After adding water, the solution was extracted with ethyl acetate, washed with saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride in this order, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the product was purified by silica gel column chromatography to obtain 1.7 g of 7-[1-(benzyloxycarbonyl)piperidine-4-yloxyacetylamino]-2-(2-(ethoxycarbonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline (yield: 90%, oily product).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[F:12][C:13]([F:23])([F:22])[CH:14]([C:16]1[O:20][N:19]=[C:18]([CH3:21])[CH:17]=1)[OH:15]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([NH2:9])=[C:2]([O:15][CH:14]([C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)[C:13]([F:12])([F:23])[F:22])[CH:7]=1
Reactant: Cc1cc(C(O)C(F)(F)F)on1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: Cc1cc(C(Oc2cc(F)ccc2N)C(F)(F)F)on1

Procedure:
Intermediate III.8 is prepared in a similar manner as intermediate III.4 from 2,4-difluoro-1-nitro-benzene and 2,2,2-trifluoro-1-(3-methylisoxazol-5-yl)ethanol.
Reaction SMILES: C([Li])CCC.C([Sn](CCCC)(CCCC)[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)CCC.[C:25]([O:29][C:30]([N:32]1[CH:37]2[CH2:38][CH2:39][CH:33]1[CH2:34][C:35](=[O:40])[CH2:36]2)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl-].[NH4+]>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH:37]2[CH2:38][CH2:39][CH:33]1[CH2:34][C:35]([OH:40])([C:11]1[N:12]=[CH:13][CH:14]=[CH:15][N:16]=1)[CH2:36]2)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ncccn1)C2
Temperature: -78 °C
Reaction time: 3 h
Yield: 40.6 %

Procedure:
n-Butyl lithium (2.5M, 1.1 mL, 2.77 mmol) was added dropwise to a solution of 2-tributylstannanyl-pyrimidine (1 g, 2.71 mmol) in THF (5 mL), under nitrogen at −78° C. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.25 g, 1.13 mmol) in THF (2 mL) was added and the reaction mixture stirred at −78° C. for 3 hours. A solution of saturated aqueous ammonium chloride was added and the mixture extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 5-30% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.14 g). LCMS m/z 306.2 [M+H]+. R.T.=3.44 min (Analytical Method 3).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:25]([CH3:26])=[CH:24][S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCc3ccc(F)cc3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2(O)[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4]([F:17])[CH:3]=1>Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH:10]=2)=[C:4]([F:17])[CH:3]=1
Reactant: CN1CCC(O)(c2cc(F)c(Br)cc2F)CC1
Agent: Cl
Product: CN1CC=C(c2cc(F)c(Br)cc2F)CC1
Yield: 112.2 %

Procedure:
A solution of 0.92 g (3 mmoles) of 4-(4-bromo-2,5-difluorophenyl)-1-methyl-4-piperidinol in 20 ml of 6 N hydrochloric acid was refluxed 4 hours, and evaporated to dryness under vacuum. The residue was stirred with ethyl ether and filtered to afford 0.97 g of the title compound; mp 223°-233° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[N:34]=1>>[Cl:1][C:2]1[CH:26]=[C:25]([O:27][C:28]([F:29])([F:31])[F:30])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:13]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][C:39]([OH:41])([CH3:40])[CH3:42])[N:34]=2)=[O:14])[C:9](=[O:11])[CH:10]=1
Reactant: O=C(O)C(CC1CCCCC1)n1ncc(Oc2ccc(OC(F)(F)F)cc2Cl)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCCC2)n2ncc(Oc3ccc(OC(F)(F)F)cc3Cl)cc2=O)n1
Yield: 52 %

Procedure:
Using the method described in Example 49, 2-[4-(2-chloro-4-trifluoromethoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclohexyl-propionic acid (Intermediate 91) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2-chloro-4-trifluoromethoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (130 mg, 52%); ES+-HRMS m/e calcd for C27H31N5O5F3Cl [M+H+] 598.2039 found 598.2038. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.84-1.26 (m, 6H), 1.05 (br. s., 6H), 1.63 (br. s., 5H), 1.74-1.91 (m, 1H), 2.07-2.23 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.48-5.60 (m, 1H), 5.91 (d, J=2.7 Hz, 1H), 6.39 (s, 1H), 7.45-7.60 (m, 2H), 7.67 (dd, J=9.1, 2.1 Hz, 1H), 7.87 (br. s., 1H), 8.22 (d, J=2.7 Hz, 1H), 10.82 (s, 1H).