Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[S:3]([N:13]1[C:17]2=[N:18][CH:19]=[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:21]=[C:16]2[CH:15]=[CH:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Br[CH2:31][C:32]([CH:34]1[CH:39]([CH3:40])[CH2:38][CH2:37][N:36]([C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[CH2:35]1)=[O:33]>CN(C=O)C>[C:25]([O:24][C:23]([N:22]([C:20]1[N:21]=[C:16]2[CH:15]=[CH:14][N:13]([S:3]([C:6]3[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=3)(=[O:5])=[O:4])[C:17]2=[N:18][CH:19]=1)[CH2:31][C:32]([CH:34]1[CH:39]([CH3:40])[CH2:38][CH2:37][N:36]([C:41]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:42])[CH2:35]1)=[O:33])=[O:29])([CH3:26])([CH3:28])[CH3:27]
Reactant: CC1CCN(C(=O)OCc2ccccc2)CC1C(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NC(=O)OC(C)(C)C)cnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)C4CN(C(=O)OCc5ccccc5)CCC4C)C(=O)OC(C)(C)C)cnc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 0.088 g, 2.2 mmol) in DMF at about 0° C. (10 mL) was added a solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.86 g, 2.2 mmol, Step F) in DMF (10 mL) and the mixture was stirred at about 0° C. for about 1 h. A solution of benzyl 3-(2-bromoacetyl)-4-methylpiperidine-1-carboxylate (0.78 g, 2.2 mmol, Step B) in DMF (5 mL) was added drop-wise and the resulting mixture was stirred at ambient temperature for about 16 h. The solvent was removed and the residue was partitioned between EtOAc and water (40 mL each). The organic phase was washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give benzyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-methylpiperidine-1-carboxylate (1.45 g, 100%): LC/MS (Table 2, Method a) Rt=3.14 min; MS m/z: 662 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[C:32]([NH2:38])=[C:31]([CH3:39])[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:38][C:32]1[C:33]([N+:35]([O-:37])=[O:36])=[CH:34][C:29]([O:28][C:24]2[N:25]=[CH:26][N:27]=[C:22]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:23]=2)=[CH:30][C:31]=1[CH3:39]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc([N+](=O)[O-])c1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c(N)c([N+](=O)[O-])c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
496 mg (1.80 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 480 mg (1.71 mmol) 4-(6-chloro-pyrimidin-4-yloxy)-2-methyl-6-nitro-phenylamine and 0.697 mL (4.00 mmol) DIPEA were combined in 10.0 mL DMF and stirred overnight at RT. The reaction mixture was added to ice water, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:8]3[CH:9]=[C:10]([C:20]4[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=4)[N:11]([CH2:16][O:17][CH2:18][CH3:19])[C:12]=3[CH:13]=[CH:14][CH:15]=2)=[O:6])[CH2:3][CH2:2]1.Cl.[NH2:29][C@@H:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[OH:35].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:26][C:25]1[C:20]([C:10]2[N:11]([CH2:16][O:17][CH2:18][CH3:19])[C:12]3[CH:13]=[CH:14][CH:15]=[C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])[C:8]=3[CH:9]=2)=[N:21][C:22]([NH:29][C@@H:30]2[CH2:34][CH2:33][CH2:32][C@H:31]2[OH:35])=[N:23][CH:24]=1
Reactant: CCOCn1c(-c2nc(Cl)ncc2Cl)cc2c(C(=O)NC3CC3)cccc21
Reactant: N[C@@H]1CCC[C@H]1O
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCn1c(-c2nc(N[C@@H]3CCC[C@H]3O)ncc2Cl)cc2c(C(=O)NC3CC3)cccc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 93.6 %

Procedure:
A mixture of N-cyclopropyl-2-(2,5-dichloropyrimidin-4-yl)-1-(ethoxymethyl)-1H-indole-4-carboxamide (30 g, 75 mmol), (1R,2R)-2-aminocyclopentanol hydrochloride (12.3 g, 90 mmol) and DIPEA (37.5 mL, 225 mmol) in DMSO (150 mL) is stirred at 80° C. for 16 h, then poured into water (1 L), and extracted with EA (2×500 mL). The combined extracts are washed with aqueous saturated sodium chloride (500 mL), dried over Na2SO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel to give 2-{5-chloro-2-[(1R,2R)-2-hydroxycyclopentylamino]pyrimidin-4-yl}-N-cyclopropyl-1-(ethoxymethyl)-1H-indole-4-carboxamide (33 g, 93%). MS (m/z): 470 (35Cl) and 472 (37Cl) (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:20]=[CH:19][N:18]=2)=[CH:12][C:11]=1[NH:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][CH:32]=1>>[CH3:8][N:5]1[CH2:6][CH2:7][N:2]([NH:1][CH2:37][C:34]2[CH:33]=[CH:32][C:31]([C:30]([NH:29][C:11]3[CH:12]=[C:13]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:14]=[CH:15][C:10]=3[F:9])=[O:39])=[CH:36][CH:35]=2)[CH2:3][CH2:4]1
Reactant: CN1CCN(N)CC1
Reactant: O=C(Nc1cc(Nc2nccc(-c3cccnc3)n2)ccc1F)c1ccc(CCl)cc1
Product: CN1CCN(NCc2ccc(C(=O)Nc3cc(Nc4nccc(-c5cccnc5)n4)ccc3F)cc2)CC1
Yield: 53.2 %

Procedure:
1-Amino-4-methylpiperazine (0.66 g, 5.77 mol) and N-[4-fluoro-3-(4-chloromethyl benzoylamino)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine (1 g, 2.31 mmol) were reacted according to the same procedure as Example 3 to give 4-(4-methylpiperazin-1-ylaminomethyl)-N-[2-fluoro-5-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (0.63 g).
Reaction SMILES: [N:1]1([C:7]2[N:21]=[C:10]3[N:11]=[CH:12][CH:13]=[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[N:9]3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH:23]([CH2:33][CH3:34])[C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:25].C(N(CC)C(C)C)(C)C>CC(O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24](=[O:25])[CH2:23][CH2:33][CH2:34][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:21]=[C:10]4[N:11]=[CH:12][CH:13]=[C:14]([C:15]5[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=5)[N:9]4[N:8]=3)[CH2:6][CH2:5]2)=[CH:31][CH:30]=1
Reactant: c1cc(-c2ccnc3nc(N4CCNCC4)nn23)ccn1
Reactant: CCC(Cl)C(=O)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(CCCN1CCN(c2nc3nccc(-c4ccncc4)n3n2)CC1)c1ccc(F)cc1
Yield: 13.5 %

Procedure:
A mixture of 5.6 g (0.02 moles) of 2-(1-piperazinyl)-7-(4-pyridyl)[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described in Example 47), 4.0 g (0.02 moles) of α-chloro-p-fluorobutyrophenone, 3.6 g (0.027 moles) of N,N-diisopropylethylamine and 100 ml of 2-propanol was heated at reflux for 16 hours with stirring. The reaction mixture was evaporated in vacuo to a solid. The solid was dissolved in 100 ml of water and extracted twice with 100 ml of chloroform. The extracts were combined, dried over magnesium sulfate, filtered and evaporated to a dark syrup. The syrup was dissolved in dichloromethane and passed through a pad of magnesium silicate, washing with methylene chloride. This filtrate was collected and set aside. Then acetone was passed through the pad and the acetone filtrate was collected and evaporated to a syrup. The syrup was dissolved in 15 ml of ethanol, 200 ml of ether was added, then hexane until cloudy. Evaporation by boiling caused crystallization. The crude product was collected and washed with ether. Recrystallization from ethanol gave 1.2 g of the desired product as yellow crystals, mp 133°-135° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[O:22])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCOCC3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and morpholine (9.9 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(morpholin-4-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (43.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:12][C:13]([F:20])([CH:17]([F:19])[F:18])[C:14](Cl)=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:8][C:14](=[O:15])[C:13]([F:20])([F:12])[CH:17]([F:19])[F:18])=[N:6][CH:7]=1
Reactant: O=C(Cl)C(F)(F)C(F)F
Reactant: Nc1ncc(Cl)cc1[N+](=O)[O-]
Product: O=C(Nc1ncc(Cl)cc1[N+](=O)[O-])C(F)(F)C(F)F

Procedure:
5-Chloro-3-nitro-2-aminopyridine is reacted with 2,2,3,3-tetrafluoropropionyl chloride to yield 5-chloro-3-nitro-2-(2,2,3,3-tetrafluoropropionamido)pyridine, which when hydrogenated yields 6-chloro-1-hydroxy-2-(1,1,2,2-tetrafluoroethyl)-1H-imidazo(4,5-b)pyridine. This compound is reacted with trimethylamine to prepare 6-chloro-1-hydroxy-2-(1,1,2,2-tetrafluoroethyl)-1H-imidazo(4,5-b)pyridine trimethylamine salt.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[CH:10]=2)[NH:5][C:4]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>Cl>[ClH:1].[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:10]=2)[NH:5][C:4]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CCc1ccc2[nH]c(-c3cccnc3)c(C)c2c1
Agent: Cl
Product: Cc1c(-c2cccnc2)[nH]c2ccc(CCC(=O)O)cc12

Procedure:
Heating a suspension of 7.5 g of ethyl 3-methyl-2-(3-pyridyl)indole-5-propionate hydrochloride in 450 ml of 2N HCl at reflux temperature for 2 hours, cooling and collecting the resulting solid gives 3-methyl-2-(3-pyridyl)-indole-5-propionic acid hydrochloride, m.p. 290°. Similar hydrolysis of ethyl 3-methyl-2-(4-pyridyl)indole-5-propionate yields 3-methyl-2-(4-pyridyl)indole-5-propionic acid hydrochloride, melting above 305°.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[OH:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2](=[O:3])([O:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: OCc1cccs1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)OCc1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Chloroethyl chloroformate (28.6 g, 0.2 mol) and 2-hydroxymethyl-thiophene (20.6 g, 0.18 mol) were dissolved in chloroform (220 ml) at 0° C. Pyridine (15.8 g, 0.2 mol) was added dropwise during 35 minutes maintaining the temperature below 10° C. After stirring at room temperature for 24 hours the precipitate was filtered off. The organic phase was washed three times with 1 normal hydrochloric acid, once with a saturated sodium hydrogen carbonate solution and finally twice with water. The organic solution was dried with magnesium sulfate and the solvent was removed at reduced pressure. The residue was distilled in vacuo. Yield: 36.5 g. 1H-NMR (DMSO-d6): delta=1.76 (CH3); 5.41 (CH2); 6.53 (CHCH3); 7.04, 7.25; 7.59 ppm (thiophene).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=2)[NH:5][CH:4]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:20]=2)[CH2:3]1.[CH:28]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:30][CH2:29]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1([CH3:27])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:34][S:31]([CH:28]3[CH2:30][CH2:29]3)(=[O:33])=[O:32])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:20]=2)[CH2:3]1
Reactant: CC1(C)CC(c2cncc(N3CCOCC3)c2)Nc2ccc(C(=O)O)cc21
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cncc(N3CCOCC3)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Yield: 15 %

Procedure:
A mixture of 4,4-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.54 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (160 mg, 0.82 mmol), 4-dimethylaminopyridine (100 mg, 0.82 mmol), cyclopropane sulfonic acid amide (196 mg, 1.62 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [4,4-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (38 mg, 15%) as a light yellow solid: MS (ESI) M+1=471.2.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[CH3:13][C:14]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C(O)C>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:14]=2[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1c(N)cccc1Cl
Solvent: CCO
Product: COC(=O)c1ccc(C=Nc2cccc(Cl)c2C)cc1
Reaction time: 0.25 h

Procedure:
p-carbomethoxybenzaldehye (0.20 moles) was treated with 2-methyl-3-chloroaniline (0.20 moles) with vigorous stirring in a 1 liter Erlenmeyer flask. After 15 mins., 33 cc of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 45 mins. The reaction mixture was left standing at room temperature for 10 min., then it was placed in an ice bath for 0.5 hours. The crystals which formed were collected, washed with 95% ethanol, and air dried. Recrystallization from 95% ethanol gave N-(p-carbomethoxybenzylidene)-2-methyl-3-chloroaniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCC(CO)CC2)nn1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCC2CCN(c3ccc(OC)nn3)CC2)cc1
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a stirred and cooled solution of 6.7 parts of 1-(6-methoxy-3-pyridazinyl)-4-piperidinemethanol, 5 parts of ethyl 4-hydroxybenzoate and 7.8 parts of triphenylposphine in 135 of tetrahydrofuran was added a solution of 5.6 parts of diethyl diazenedicarboxylate in 45 parts of tetrahydrofuran. Upon complete addition, stirring was continued overnight at room temperature. After evaporation, the residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and ethanol (99.5:0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 6.7 parts (60.1%) of ethyl 4-[[1-(6-methoxy-3-pyridazinyl)-4-piperidinyl]methoxy]benzoate; mp. 147.2° C. (comp. 142).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:23]=[CH:22][C:11]3[CH:12]([NH:15][C:16]([C:18]4([NH2:21])[CH2:20][CH2:19]4)=[O:17])[CH2:13][O:14][C:10]=3[CH:9]=2)[CH:7]=1.[N:31]1[CH:36]=[CH:35][C:34]([C:37](O)=[O:38])=[CH:33][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:23]=[CH:22][C:11]3[CH:12]([NH:15][C:16]([C:18]4([NH:21][C:37]([C:34]5[CH:35]=[CH:36][N:31]=[N:32][CH:33]=5)=[O:38])[CH2:20][CH2:19]4)=[O:17])[CH2:13][O:14][C:10]=3[CH:9]=2)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)OCC3NC(=O)C2(N)CC2)no1
Reactant: O=C(O)c1ccnnc1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)OCC3NC(=O)C2(NC(=O)c3ccnnc3)CC2)no1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-6-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-2,3-dihydro-benzofuran-3-yl}-amide (example 45) has been coupled with pyridazine-4-carboxylic acid to yield the title compound as yellow solid. MS: 535.1 (MH+, 1Cl).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.CN(C)[CH:16]=[O:17].[BH4-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:16][OH:17])=[N:8][CH:9]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: OCc1ccc(F)cn1
Temperature: 25 °C

Procedure:
Add butyllithium (10.9 mL, 27.22 mmol, 2.5 M solution in hexanes) to a −78° C. solution of 2-bromo-5-fluoro-pyridine (3.99 g, 22.68 mmol) in toluene (200 mL). Stir the reaction at −78° C. for 90 min and then add N,N-dimethylformamide (2.3 mL, 29.71 mmol) via syringe. Stir the reaction for an additional 2 h at −78° C. and then add sodium borohydride (1.72 g, 45.36 mmol) and allow the reaction to warm to room temperature over a 12 h period. Quench the reaction with saturated aqueous sodium bicarbonate (20 mL) and dilute with ethyl acetate (100 mL). Separate the organic phase and dry (magnesium sulfate), filter and concentrate in vacuo to give a yellow oil. Purify the oil by column chromatography (silica gel; 10% to 50% ethyl acetate in hexanes) to give 1.30 g (45%) as a clear colorless oil. 1H NMR (300 MHz, CDCl3): δ 8.41s, 1H), 7.46-7.37 (m, 1H), 7.32-7.27 (m, 1H), 4.75 (s, 2H), 3.64 (br s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]2)[CH2:3][CH2:2]1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)=[CH:25][CH:24]=1)=[O:21]>>[F:38][C:36]([F:37])([F:39])[C:33]1[CH:34]=[CH:35][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:20]([N:1]3[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH:10]4[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][OH:18])[CH2:14][CH2:15]4)[CH2:3][CH2:2]3)=[O:21])=[CH:24][CH:25]=2)=[N:31][CH:32]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: OCCN1CCC(CCCC2CCNCC2)CC1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(CCCC2CCN(CCO)CC2)CC1

Procedure:
The title product was prepared from 2-[4-(3-piperidin-4-yl-propyl)-piperidin-1-yl]-ethanol and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate. The reaction mixture was evaporated, diethyl ether (30 ml) was added and the title product isolated by filtration, washed with diethyl ether and dried to give (67%, white solid. HPLC-MS m/z=(M+1) 536.2, Rt: 3.39 min.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[NH3:15]>C(O)C>[NH2:15][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: N
Reactant: CNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Solvent: CCO
Product: CNc1c([N+](=O)[O-])ccc(N)c1C#N
Temperature: 25 °C
Yield: 95 %

Procedure:
A suspension of the above amine (30.0 g, 142 mmol) in a 5.3 M solution of ammonia in ethanol (200 mL) was heated in a sealed stainless steel reaction vessel (600 mL capacity) at 90° C. for 24 h. The reaction vessel was cooled to room temperature, then to 0° C., and opened. The product was filtered, washed with ethanol (30 mL) and dried to give 6-amino-2-methylamino-3-nitro-benzonitrile (25.94 g, 95%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:18]1([CH3:23])OCC[O:19]1)[C:14]([O:16][CH3:17])=[O:15])[C:5]2=[O:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:18](=[O:19])[CH3:23])[C:14]([O:16][CH3:17])=[O:15])[C:5]2=[O:24]
Reactant: COC(=O)C(CN1C(=O)c2ccc(C)cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)C(CN1C(=O)c2ccc(C)cc2C1=O)C(C)=O

Procedure:
Methyl 2-(5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (23 mg, 26%) in the same manner as described in the above example 6 (1) from methyl 3-(5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.10 g, 0.30 mmol) and p-toluenesulfonic acid monohydrate (10 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH:14]1[CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]1[CH2:17][CH2:16][CH2:15]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
A mixture of methyl 3-bromo-4-hydroxybenzoate (Description 64, 2.3 g, 10 mmol), bromocyclobutane (2.0 g, 15 mmol) and potassium carbonate (2.42 g, 17.5 mmol) in DMF (25 ml) was stirred at room temperature for 3 days then at 70° C. for 6 h. The mixture was cooled, diluted with water (150 ml) and extracted with ethyl acetate (4×25 ml). The combined organic fractions were washed with aqueous sodium hydroxide (1M, 25 ml), dried (MgSO4), and the solvent was evaporated under reduced pressure to give the title compound as a gum (1.15 g). 1H NMR (CDCl3) δ 1.66-1.77 (1 H, m), 1.88-1.93 (1 H, m), 2.22-2.31 (2 H, m), 2.46-2.60 (2 H, m), 3.89 (3 H, s), 4.75 (1 H, app. pent, J 7.0 Hz), 6.74 (1 H, d, J 8.6 Hz), 7.91 (1 H, dd, J 8.6, 2.1 Hz), and 8.23 (1 H, d, J 2.1 Hz).
Reaction SMILES: [N+]([O-])(O)=O.[Br:5][C:6]1[S:10][C:9](N)=[N:8][C:7]=1[CH:12]([CH3:14])[CH3:13].P(=O)(O)(O)O.N([O-])=O.[Na+].O[PH2]=O>O>[Br:5][C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)c1nc(N)sc1Br
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: O=[PH2]O
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC(C)c1ncsc1Br
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 12.7 %

Procedure:
Concentrated nitric acid (4 mL) was slowly added to 5-bromo-4-isopropyl-thiazol-2-ylamine (2.05 g, 9 mmol), and concentrated phosphoric acid (14 mL) was added dropwise over five minutes. The mixture was cooled to −5° C., and a solution of sodium nitrite (0.768 g, 11 mmol) in 5 mL water was added dropwise over a 15 minute period. The reaction mixture was stirred at −5° C. for 30 minutes, and an aqueous solution of H3PO2 (6 mL, 50% weight in water) was slowly added. The reaction mixture was stirred at −5° C. for 2.5 hours, then stirred at room temperature for 18 hours. The reaction mixture was cooled to 0° C. and quenched by addition of aqueous NaOH (30% weight solution). The mixture was extracted with methylene chloride, and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting oil was chromatographed (10% EtOAc in hexanes) to give 236 mg of 5-bromo-4-isopropyl-thiazole as an oil, MS (M+H)=207.