Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:23])[CH:21]=[CH2:22])[CH2:16][CH:15]=3)[S:13][C:6]=12.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:23])[CH2:21][CH2:22][NH:35][CH2:34][CH2:33][O:32][CH3:31])[CH2:16][CH:15]=3)[S:13][C:6]=12
Reactant: COCCN
Reactant: C=CC(=O)N1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCNCCC(=O)N1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Yield: 44.5 %

Procedure:
A solution of the compound 98 (171.0 mg, 0.4 mmol) and 2-methoxyethanamine (0.14 mL, 1.62 mmol) in THF (98.1 mL) was stirred overnight at room temperature. It was then diluted with DCM, washed with aqueous sodium bicarbonate and water. The organic phase was extracted with 1N HCl, the aqueous acidic phase was basified by addition of 1N NaOH (pH˜11) and extracted with DCM. The DCM extract was dried over anhydrous sodium sulphate and concentrated under reduced pressure affording title compound 99 (89.0 mg, 45% yield) as cream foam. MS (m/z): 501.2 (M+1).
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1.[Cl:14][C:15]1[C:16]([CH2:25][CH:26]([NH:28][CH:29]2[CH2:31][CH2:30]2)[CH3:27])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C>O1CCCC1>[Cl:14][C:15]1[C:16]([CH2:25][CH:26]([N:28]([CH:29]2[CH2:31][CH2:30]2)[C:8]([C:7]2[C:3]([CH:2]([F:13])[F:1])=[N:4][N:5]([CH3:12])[C:6]=2[F:11])=[O:9])[CH3:27])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: CC(Cc1ncc(C(F)(F)F)cc1Cl)NC1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Cc1ncc(C(F)(F)F)cc1Cl)N(C(=O)c1c(C(F)F)nn(C)c1F)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.9 %

Procedure:
At ambient temperature, a solution of 74 mg (0.35 mmol) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride in 2 ml of tetrahydrofurane is added dropwise to a solution of 100 mg (0.317 mmol) of N-{1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]propan-2-yl}cyclopropanamine and 0.137 ml (0.984 mmol) of triethylamine in 3 ml of tetrahydrofurane. The reaction mixture is stirred for 15 hrs at ambient temperature. The solvent is removed under vacuum and 50 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×25 ml) and the combined organic layers are successively washed by a 1 N solution of HCl, a saturated solution of potassium carbonate and brine and dried over magnesium sulfate to yield after concentration 131 mg of an oil. Column chromatography on silica gel (gradient heptane/ethyl acetate) yields 72 mg (47% yield) of N-{1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]propan-2-yl}-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide as a colorless oil (M+H=455).
Reaction SMILES: C(O[C:6](=[O:36])[NH:7][C@H:8]([C:12](=[O:35])[NH:13][C@H:14]([B:22]1[O:30][C@H:29]2[C@:24]([CH3:34])([C@H:25]3[CH2:31][C@@H:27]([CH2:28]2)[C:26]3([CH3:33])[CH3:32])[O:23]1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.[C:37]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C@@H:44]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)C(O)=O)[CH:38]=1>>[C:37]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C@@H:44]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:6]([NH:7][C@@H:8]([CH:9]([CH3:11])[CH3:10])[C:12]([NH:13][C@H:14]([B:22]2[O:30][C@H:29]3[C@:24]([CH3:34])([C@H:25]4[CH2:31][C@@H:27]([CH2:28]3)[C:26]4([CH3:33])[CH3:32])[O:23]2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:35])=[O:36])[CH:38]=1
Reactant: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)C(C)C)cc1

Procedure:
The title compound is prepared as described in example 1 but using {(S)-2-Methyl-1-[(R)-2-phenyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-propyl}-carbamic acid tert-butyl ester and (S)-2-(Biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([I:13])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)c1cc(Cl)c(C)cc1O
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(C)c(I)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethanone (20 g, 110 mmol) in acetic acid (200 mL) was added N-iodosuccinimide (29 g, 130 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, neutralized with saturated sodium bicarbonate, filtered off insoluble succinimide and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was recrystallized from a mixture of ethyl acetate and hexane (25.8 mg, 77%). LCMS calculated for C9H9ClIO2 (M+H)+: m/z=311.0. found: 311.0.
Reaction SMILES: [C:1]1([CH3:35])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.O>[C:1]1([CH3:35])[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)CCC3)cc1
Temperature: 50 °C
Reaction time: 7.5 h

Procedure:
Ethyl 7-(2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) was dissolved in THF (94 ml) and lithium hydroxide monohydrate (7.79 g, 186 mmol) in water (94 ml) was added dropwise. The reaction mixture was warmed to 50° C. and stirred for 7.5 hours. The reaction mixture was concentrated in vacuo to remove the THF and diluted with water (500 ml). The pH of the aqueous layer was adjusted to pH 2 with 1 N HCl (100 ml) and extracted with EtOAc (3×500 ml). The combined organic layers were washed with brine (200 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude solid was suspended in TBME/hexane (1:1, 100 ml) and rotated on the rotary evaporator (no vacuum) at RT until crystals formed. The solid was removed by filtration, washed with heptanes (50 ml) and dried at RT overnight. The solid was re-crystallized from a hot mixture of EtOH (211 ml) and water (159 ml). After seeding and stirring for 1 h at 5° C., the crystals were filtered off and the product dried overnight at 40° C. in a vacuum oven to afford the title compound; See Table 4 for characterising data.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[CH:20]=[CH:21][C:22](O)=O>>[CH3:29][O:28][C:26]1[CH:25]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[CH:27]=1)/[CH:20]=[CH:21]/[C:22]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(OC)cc(OC)c3)nc2n(CC)c1=O
Yield: 49 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.48 g (16.7 mmol) of 3,5-dimethoxy-cinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 2.74 g (yield 49%) of Compound 129 as a white powder.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:20](O)=O.[N:27]1C=CC=CC=1>>[Cl:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:20]#[N:27]
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: c1ccncc1
Agent: CS(=O)(=O)Cl
Product: N#Cc1cc2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
Methanesulphonyl chloride (1 ml) added to a solution of N-(3,4-dichlorobenzyl)indole-2-carboxylic acid (0.23 g) in pyridine at 0° C., and reaction stirred for 2 hours. Ammonia gas was then bubbled through the reaction mixture for 15 mins and then concentrated in vacuo. The residue was dissolved in fresh pyridine, cooled to 0° C. and methanesulphonyl chloride (1 ml) added dropwise. The reaction was stirred for 16 hours, then concentrated in vacuo and residue partitioned between 1N HCl and dichloromethane. Combined organic extracts were dried (MgSO4) and concentrated and the resulting solid purified by column chromatography using dichloromethane-10% ethyl acetate as eluent to give N-(3,4-dichlorobenzyl)-2-cyanoindole as yellow crystals (58 mg, 27%); NMR δ (CD3SOCD3) 5.82 (s, 2H), 6.95-7.70 (m, 7H), 8.03 (m, 1H); M/z (+) 300 (M+), 161, 159; followed by N-(3,4-dichlorobenzyl)indole-2-carboxamide as yellow crystals (37 mg, 16%); M/z (+) 318 (M+), 274, 161, 159, 71, 57.
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:1]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CC=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CCN1CCCC1
Reaction time: 24 h

Procedure:
500 mL tetrahydrofuran (THF) was placed in a 1-L suction flask. 35.3 g isovaleraldehyde (0.41 mol) and then 28.4 g pyrrolidine (0.40 mol) were mixed into the THF. 100 g of sodium triacetoxyborohydride (0.47 mol) powder was then added in 5-10 g increments to the solution. During the addition vigorous stirring was used to ensure that the powder did not clump at the bottom of the flask which would prevent the efficient mixing of the suspension. After each addition of the sodium triacetoxyborohydride powder, adequate time was provided to form a uniform slurry before the next addition of the powder. After one day the product was worked up by quenching the suspension with the slow addition of 291 g of a 27% KOH solution. The product was then extracted from the resultant solution with 500 mL pentane. The organic fraction was then collected with a separatory funnel and dried with anhydrous magnesium sulfate. The N-isopentylpyrrolidine product was then isolated by rotary evaporation of the THF and pentane solvents under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19]O)[N:10]=2)=[CH:4][CH:3]=1.CS([Cl:25])(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:25][CH2:19][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH:17]=[CH:18][C:9]([NH:8][CH2:7][C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[N:10]2
Reactant: Cc1ccc(CNc2ccc3c(CO)cccc3n2)o1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNc2ccc3c(CCl)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinolin-5-yl}-methanol (example 41, step A, 70 mg, 0.261 mmol) was dissolved in 2 mL tetrahydrofurane and methanesulfonyl chloride (34 mg, 0.297 mmol) and N,N-diisopropyl ethyl amine (41 mg, 0.318 mmol) were added. The reaction mixture was stirred at room temperature overnight and the solvent was evaporated off. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). (5-Chloromethyl-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine was obtained as a brown solid (59 mg, 79%), MS: m/e=287.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16](=[CH:21][CH:22]=1)[C:17]([O:19]C)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16](=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(C(=O)O)c(OCc2ccccc2)c1)OCc1ccccc1
Temperature: 75 °C
Yield: 90 %

Procedure:
Methyl N-(benzyloxycarbonyl)-4-aminomethyl-2-O-benzylsalicylate (6.81 g, 16.8 mmoles) was dissolved in tetrahydrofuran (50 mL). A solution of lithium hydroxide monohydrate (0.78 g, 18.5 mmoles) in water (25 mL) was added, and the reaction mixture was stirred and heated at 75° C. for 24 hours. The solution was cooled, and 1N aqueous hydrochloric acid (50 mL) was added. The reaction mixture was extracted twice with ethyl acetate (150 mL then 50 mL). The combined ethyl acetate extracts were washed with water (75 mL) and saturated aqueous sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to 150 mL. The ethyl acetate solution was heated to boiling, and hexanes (150 mL) was added. The solution was cooled in ice, and crystals formed. The crystals were collected by filtration, washed with hexanes, and dried in vacuo to afford 5.92 g (90% yield) of N-(benzyloxy-carbonyl)-4-aminomethyl-2-O-benzylsalicylic acid (m.p. 139°-140° C., open capillary, uncorrected).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14]([CH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[CH:13][CH:12]=2)[C:8]([O:22][CH3:23])=[CH:7][N:6]=1)(=O)=O.[CH3:24][C:25]1([CH3:34])[CH2:30][CH:29]([NH2:31])[CH2:28][C:27]([CH3:33])([CH3:32])[NH:26]1.CCN(C(C)C)C(C)C>CO>[CH3:23][O:22][C:8]1[C:9]([C:11]2[S:15][C:14]([CH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[CH:13][CH:12]=2)=[N:10][C:5]([NH:31][CH:29]2[CH2:30][C:25]([CH3:34])([CH3:24])[NH:26][C:27]([CH3:33])([CH3:32])[CH2:28]2)=[N:6][CH:7]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: COc1cnc(S(C)(=O)=O)nc1-c1ccc(CCC(C)(C)O)s1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(NC2CC(C)(C)NC(C)(C)C2)nc1-c1ccc(CCC(C)(C)O)s1
Temperature: 120 °C

Procedure:
4-[5-(2-Methanesulfonyl-5-methoxy-pyrimidin-4-yl)-thiophen-2-yl]-2-methyl-butan-2-ol (240 mg, 0.673 mmol) was mixed with 2,2,6,6-Tetramethyl-piperidin-4-ylamine (0.5 ml, 2.86 mmol) and DIEA (0.5 ml, 2.92 mmol) and heated to 120° C. in a closed flask for 2 hours. The residue was then diluted with MeOH and purified by preparative HPLC to give the title compound. Yield: 8 mg (3%).
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][CH:29]1[CH2:31][CH2:30]1.N([O-])=O.[Na+].CC#N.O.[ClH:40]>O.Cl[Cu]>[Cl:40][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][CH:29]1[CH2:31][CH2:30]1
Reactant: CCOC(=O)C1(c2cc(OCC3CC3)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(c2cc(OCC3CC3)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Temperature: 70 °C
Reaction time: 0.67 h

Procedure:
Ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.280 g, 0.64 mmol) was dissolved in a mixture of MeCN/H2O/HCl 10 mL/10 mL/4 mL at 0° C. A solution of NaNO2 (0.066 g, 0.96 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (0.32 g, 3.2 mmol) in water (2 mL) was added drop wise at 0° C. The reaction mixture was heated to 70° C. for 1 h and the solvent was evaporated under reduced pressure. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.10 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH:16]([CH3:18])[NH:15][CH:14]([CH3:19])[CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:13][CH:14]([CH3:19])[N:15]([C:28]([NH:27][C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)=[O:29])[CH:16]([CH3:18])[CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1CN(c2ccnc3cc(Cl)ccc23)CC(C)N1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CO
Product: CC1CN(c2ccnc3cc(Cl)ccc23)CC(C)N1C(=O)Nc1ccc(F)cc1

Procedure:
7-Chloro-4-(3,5-dimethylpiperazin-1-yl)quinoline (100 mg, 0.36 mmol) and 4-fluorophenyl isocyanate (70 mg, 0.51 mmol) are reacted according to method C yielding the title product as colorless solid after column chromatography with CH2Cl2-MeOH.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:24])[C@H:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH3:16])C1C=CC=CC=1.[BH4-].[Na+]>C1COCC1.O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:15]([CH3:16])[CH2:14][OH:24])=[CH:22][CH:21]=1
Reactant: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
To a room-temperature solution of (S)-4-benzyl-3-((S)-2-(4-fluorophenyl) propanoyl)oxazolidin-2-one (1.8 g, 5.5 mmol, 1.0 equiv) in THF (18 mL) was added a solution of NaBH4 (1.0 g, 26.4 mmol, 4.8 equiv) in water (6 mL). The reaction mixture was stirred for 3 h at room temperature and then quenched by the careful addition of aq. 1 M HCl. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the organic layer was subsequently washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (10-75% EtOAc/Hexanes) provided the title compound (0.824 g, 97%) which was characterized by 1H NMR.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.[H-].[Na+].Cl[C:12]1[C:13]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[N:17]=1.O>CN(C=O)C>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:12]2[C:13]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)[N:17]=2)=[N:5][CH:4]=[N:3]1
Reactant: Cn1ncnc1CO
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3)nnc2cc1N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (2-methyl-2H-1,2,4-triazol-3-yl)methanol (2.5 g, 0.022 mol; EP-A-421210) in DMF (200 ml) was added a 60% suspension of sodium hydride in mineral oil (1.2 g, 0.031 mol), and the resultant slurry was stirred at room temperature under nitrogen for 1 h. 6-Chloro-3-phenyl-7-(pyrrolidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine (6.0 g, 0.020 mol) was added, and the mixture was stirred as before for 30 min. Water (600 ml) was added, precipitating a solid. This was filtered off, then washed with water and diethyl ether. The crude product was dissolved in a mixture of ethanol (50 ml) and dichloromethane (110 ml), and then the chlorinated solvent was boiled off. The resultant solution was cooled to 4° C. precipitating the title compound as a white solid (6.3 g, 83%). 1H NMR (400 MHz, CDCl3) δ1.97 (4H, m), 3.47 (4H, m), 3.97 (3H, s), 5.59 (2H, s), 6.72 (1H, s), 7.48 (3H, m), 7.95 (1H, s), 8.28 (2H, m); MS (ES+) m/e 377[MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[N:11]2[C@H:14]([C:18]([O:20]C(C)(C)C)=[O:19])[CH2:15][CH2:16][CH2:17][N:10]2[C:9](=[O:25])[CH2:8][CH2:7]1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[N:11]2[C@H:14]([C:18]([OH:20])=[O:19])[CH2:15][CH2:16][CH2:17][N:10]2[C:9](=[O:25])[CH2:8][CH2:7]1)=[O:4]
Reactant: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)OC(C)(C)C)N2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1S,9S)-tert-butyl 9-(methoxycarbonylamino)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (1.25 g, 3.52 mmol) dissolved into methylene chloride (10 mL) was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 1 h and concentrated in vacuo. Toluene (5 mL) was added and the reaction concentrated in vacuo to afford (1S,9S)-9-(methoxycarbonylamino)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid as a white solid, (587 mg, 68%): ESI-LRMS m/e calcd for C12H17N3O6[M+] 299. found 300 [M+H+].
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:34]#[C:35][CH2:36][CH3:37])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([C:34]#[C:35][CH2:36][CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCC#C[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC#C[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 18 h
Yield: 57.3 %

Procedure:
To a stirred solution of 24.3 (0.050 g, 0.10 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting mixture was stirred for 18 hours. The resulting mixture was then concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 24 (28 mg, 57% yield) as a colorless oil. MS ESI (neg.) m/e: 487.1 (M−H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[C:13]([CH3:14])=[N:12][CH:11]=[N:10]1)[NH2:5].[C:15](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:16]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:5]=[C:15]=[S:16])[CH:6]=[CH:7][C:8]=1[N:9]1[C:13]([CH3:14])=[N:12][CH:11]=[N:10]1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1ncnn1-c1ccc(N)cc1F
Solvent: ClCCl
Product: Cc1ncnn1-c1ccc(N=C=S)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
Step C (3): Dichloromethane (125 mL) was added to a flask charged with 3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (3.14 g, 16.3 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (3.79 g, 16.3 mmol). The resulting mixture was stirred for 24 h at rt and concentrated in vacuo. The crude residue was purified using silica gel chromatography (0-5% EtOAc/chloroform, linear gradient) to afford 1-(2-fluoro-4-isothiocyanatophenyl)-5-methyl-1H-1,2,4-triazole (3.18 g, 13.6 mmol, 83% yield) as a white solid. LC-MS (M+H)+ 235.0. 1H NMR (500 MHz, chloroform-d) δ ppm 7.99 (s, 1 H) 7.47 (t, J=8.24 Hz, 1 H) 7.13-7.22 (m, 2 H) 2.43 (d, J=1.83 Hz, 3H).