Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Cl:13][C:14]1[N:23]=[C:22](Cl)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>O1CCCC1>[Cl:13][C:14]1[N:23]=[C:22]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Clc1nc(-n2ccnc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a suspension of 60% sodium hydride (426 mg) in tetrahydrofuran (4 mL)-N,N-dimethylformamide (24 mL) was added imidazole (725 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise a tetrahydrofuran solution (35 mL) of 2,4-dichloroquinazoline (2.12 g) synthesized according to the method of H. C. Scarborough et al. (Journal of Organic Chemistry, 1962, pp. 957-961), in ice-acetone bath, and the mixture was stirred for 30 minutes. The reaction mixture was poured into ice-cold water, and precipitated powder was collected by filtration, washed with water and dried. The obtained powder was purified by silica gel column chromatography, (ethyl acetate), to give 1.88 g of 2-chloro-4-(1-imidazolyl)-quinazoline as colorless crystals (yield 77%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:12])=[CH:10][CH:11]=1)(=[O:5])=[O:4].C1N=CN([C:21](N2C=NC=C2)=[O:22])C=1>CC#N>[F:15][C:2]([F:14])([F:1])[S:3]([C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:21](=[O:22])[NH:13][C:8]=2[CH:7]=1)(=[O:4])=[O:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1N
Solvent: CC#N
Product: O=c1[nH]c2ccc(S(=O)(=O)C(F)(F)F)cc2[nH]1

Procedure:
Reflux 4-trifluoromethylsulfonyl-benzene-1,2-diamine (420 mg) and CDI (284 mg) for 16 hours in CH3CN (30 mL). Evaporate the solvent in vacuo. Purify by flash chromatography (1:1 hexanes/EtOAc) to obtain 5-trifluoromethylsulfonyl-1,3-dihydro-benzimidazol-2-one.
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[Br:15][C:16]1[C:17]([CH3:25])=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=O.[CH3:26][C:27]([N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)([CH3:36])[CH:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[N-]=C=O>C(Cl)Cl.C1COCC1.CN1C(=O)CCC1>[Br:15][C:16]1[C:17]([CH3:25])=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH:35][CH:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:27]([CH3:36])([N:37]1[CH2:38][CH2:39][CH2:40][CH2:41]1)[CH3:26])=[O:21]
Reactant: CC(C)(C(N)c1ccccc1)N1CCCC1
Reactant: Cc1c(Br)cccc1C(=O)O
Agent: On1nnc2cccnc21
Agent: [N-]=C=O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1c(Br)cccc1C(=O)NC(c1ccccc1)C(C)(C)N1CCCC1
Yield: 83.8 %

Procedure:
To PS-EDC (0.068 g; 0.1 mmol; 1.42 mmol/g) was added a solution of HOAt (0.01 mmol in 0.8 ml (THF:DCM, 1:1)) followed by the addition of 3-bromo-2-methyl-benzoic acid (0.011 g; 0.05 mmol) in 1:3 NMP:THF (0.25 ml) and then [2-methyl-1-phenyl-2-(1-pyrrolidinyl)propyl]amine D5 (0.011 g 0.05 mmol) in DCM (0.25 ml). The reaction was allowed to mix for 60 h. Following this PS-isocyanate (0.068 g, 0.1 mmol, 1.5 mmol/g) and PS—CO3 (0.068 g, 0.1 mmol, 1.5 mmol/g) were added and allowed to mix for another 24 h. The reaction mixture was filtered and passed through an SCX block (500 mg) (pre-wetted with DCM). The content of the Robbins block was washed with more solvent (DCM:THF, 1:1) and allowed to pass through the SCX which was then washed with DCM (2 ml×2) and methanol (2 ml×2). The SCX was then eluted with 0.5M ammonia in methanol and the product containing eluent evaporated to afford the title product (17.4 mg; 84%). Mass Spectrum (Electrospray LC/MS): Found 414 (MH+). C22H2779BrN2O requires 415; Ret. time 2.64 min*
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.O.CN(C)[CH:25]=[O:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:25](=[O:26])[NH:13][N:12]=[C:10]3[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: CN(C)C=O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1
Solvent: O
Product: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=CC2
Reaction time: 16 h

Procedure:
3 g of 7-chloro-5-(2-fluorophenyl)-2-hydrazino-3H-1-benzazepine are dissolved in 40 ml of dimethylformamide. After adding 3.6 g of N,N'-carbonyldiimidazole, the mixture is stirred at 50° for 16 hours. The solution obtained is then poured into 700 ml of water and extracted with ethyl acetate. The organic extracts are washed with water and saturated sodium chloride solution, dried and evaporated. The residue is chromatographed on 200 g of silica gel while eluting with chloroform/ethanol (98.5:1.5). After recrystallization from diisopropyl ether, there is obtained 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-1H-s-triazolo[4,3-a][1]benzazepin -1-one of melting point 223°-225°.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:32])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[C@H:28]([CH2:29][OH:30])[CH2:27][O:26][C:25]5=[O:31])=[N:22][CH:23]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:33]I>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:32])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[C@H:28]([CH2:29][O:30][CH3:33])[CH2:27][O:26][C:25]5=[O:31])=[N:22][CH:23]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)nc2)CC1
Reactant: CI
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)cn1

Procedure:
By reaction and treatment in the same manner as in Example 73 and using (R)-3-{5-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-4-hydroxymethyloxazolidin-2-one (144 mg) described in Example 245 and methyl iodide (38 μL), the title compound (85 mg) was obtained.
Reaction SMILES: [N:1]([C@@H:4]([CH3:21])[C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]([CH3:21])[C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C[C@H](N=[N+]=[N-])[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Yield: 77.5 %

Procedure:
A solution of tert-butyl (2S,3S)-3-azido-1-cyclohexylbutan-2-ylcarbamate (0.215 g, 0.73 mmol) in methanol (10 mL) was added to wetted Pd/C (0.1 g) and was hydrogenated with a balloon overnight. The reaction mixture was filtered through a pad of Celite and the solvent was removed to give tert-butyl (2S,3S)-3-amino-1-cyclohexylbutan-2-ylcarbamate (0.153 g, 78%), which was used in the next step without purification.
Reaction SMILES: C([C:5]1([OH:17])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[CH:10][CH:11]=2)[O:6]1)CCC.CS([O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH:27]([C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)[CH2:26][CH2:25]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH2:12]([O:17][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([O:22][CH2:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([C@H:30]4[CH2:35][CH2:34][C@H:33]([CH2:36][CH3:37])[CH2:32][CH2:31]4)[CH2:26][CH2:25]3)[CH:11]=2)[O:6]1)[CH2:7][CH2:8][CH3:9]
Reactant: CC[C@H]1CC[C@H](C2CCC(COS(C)(=O)=O)CC2)CC1
Reactant: CCCCC1(O)CCc2ccc(F)c(F)c2O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOC1CCc2cc(OC[C@H]3CC[C@H]([C@H]4CC[C@H](CC)CC4)CC3)c(F)c(F)c2O1

Procedure:
To 20.5 g of 2-butyl-7,8-difluorochroman-2-ol which was dissolved in 70 mL of DMF, 25 g of 4-(trans-4-ethylcyclohexyl)cyclohexylmethyl methanesulfonate and 11.4 g of anhydrous potassium carbonate were added, and heated to reflux for 3 hours. The reaction solution was poured into 10% hydrochloric acid, stirred for a while, and extracted with toluene. An organic layer was washed using 10% hydrochloric acid twive, water, a 5% sodium hydroxide aqueous solution twice, water, a saturated sodium hydrogen carbonate aqueous solution twice, and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the obtained brown solid material was purified by carrying out column chromatography (silica gel, hexane/toluene), recrystallization (hexane), recrystallization (acetone), and recrystallization (acetone), to obtain 14.7 g of 2-butoxy-7,8-difluoro-6-(trans-4-(trans-4-ethylcyclohexyl)cyclohexylmethoxy) chroman (If) as a colorless crystal.
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[ClH:29]>C(Cl)Cl.O1CCOCC1>[O:23]1[CH2:24][CH2:25][CH2:26][N:20]([C:13]2[N:14]3[C:18]([N:19]=[C:11]4[CH2:10][CH2:9][NH:8][CH2:28][CH2:27][C:12]=24)=[CH:17][CH:16]=[N:15]3)[CH2:21][CH2:22]1.[ClH:29]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CCCOCC3)c2CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cc2nc3c(c(N4CCCOCC4)n2n1)CCNCC3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 88 mg (0.23 mmol) 10-[1,4]oxazepan-4-yl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 3 mL DCM, was added 1.13 mL (4.5 mmol) HCl in dioxane (4 M), and the reaction was stirred at room temperature for 16 hours. The solvent was evaporated to give the desired product as a HCl salt.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[N:16]=[CH:17][NH:18][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[O:7]2)[CH2:3][CH2:2]1.[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[CH3:32])([CH3:21])[CH3:20].C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:1]2[CH2:6][CH2:5][C:4]3([C:15]4[N:16]=[CH:17][NH:18][C:14]=4[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[O:7]3)[CH2:3][CH2:2]2)=[O:28])=[CH:25][C:24]=1[CH3:32])([CH3:21])[CH3:20]
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1nc[nH]c1-2
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2[nH]cnc23)ccc1OC(C)C
Reaction time: 16 h
Yield: 12 %

Procedure:
A mixture of 1H-spiro[chromeno[3,4-d]imidazole-4,4′-piperidine] (210 mg, 0.88 mmol), 4-isopropoxy-3-methyl-benzoic acid (170 mg, 0.89 mmol), triethylamine (370 μL, 2.6 mmol), and EDCI (170 mg, 0.89 mmol) in dichloromethane (5 mL) was stirred for 16 h. The reaction mixture was diluted with dichloromethane and was washed with 1 M HCl, saturated solution of NaHCO3, and brine. The organics were dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography eluting with 0-100% methanol in dichloromethane to yield (4-isopropoxy-3-methylphenyl)(1H-spiro[chromeno[3,4-d]imidazole-4,4′-piperidine]-1′-yl)methanone (44 mg, 12%). ESI-MS m/z calc. 417.5, found 418.5 (M+1)+; Retention time: 1.44 minutes (3 min run).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][Si:14](Cl)([CH3:16])[CH3:15].[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23][N:24]([CH2:31][C@@:32]12[C@@H:49]3[C@H:40]([C@H:41]4[C@@:45]([CH2:47][CH2:48]3)([CH3:46])[C:44](=[O:50])[CH2:43][CH2:42]4)[CH2:39][CH2:38][C:37]1=[CH:36][C:35](=[O:51])[CH2:34][CH2:33]2)[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27]>O1CCCC1.CCCCCC.C(N(CC)CC)C>[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23][N:24]([CH2:31][C@@:32]12[C@@H:49]3[C@H:40]([C@H:41]4[C@@:45]([CH2:47][CH2:48]3)([CH3:46])[C:44]([O:50][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:43][CH2:42]4)[CH2:39][CH2:38][C:37]1=[CH:36][C:35]([O:51][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:34][CH2:33]2)[C:25](=[O:30])[C:26]([F:27])([F:28])[F:29]
Reactant: COCCOCN(C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12)C(=O)C(F)(F)F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COCCOCN(C[C@]12CC=C(O[Si](C)(C)C)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(O[Si](C)(C)C)=CC[C@@H]12)C(=O)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.15 h

Procedure:
To a stirred solution of diisopropylamine (1.03 ml, 7.34 mmole) in tetrahydrofuran (65 ml) under argon and cooled to -20° C. was added n-butyl lithium (2.76 ml of a 2.42M solution in hexane, 6.67 mmole). After 9 minutes, a cooled (-20° C.) solution of trimethysilyl chloride (2.82 ml, 22.24 mmole) in tetrahydrofuran (10 ml) was added slowly. After 2 minutes more, a cooled (-20° C.) solution of 19-[N-[(2-methoxyethoxy)methyl]trifluoroacetamido]androst-4-ene-3,17-dione (1.08 g, 2.22 mmole) in tetrahydrofuran (10 ml) was added dropwise. The reaction was stirred at -20° C. for 30 minutes and then allowed to warm slowly to room temperature. After 30 minutes at room temperature, triethylamine (10 ml) was added then ethyl ether (350 ml) and the organics washed with saturated sodium bicarbonate (2×100 ml), 150 ml of water-saturated aqueous sodium bicarbonate (2:1) and finally 100 ml of brine-saturated aqueous sodium bicarbonate (3:1). Drying (Na2SO4) and concentration gave 19-[N-[(2-methoxyethoxy)-methyl]trifluoroacetamido]-3,17-bis(trimethylsilyloxy)androsta-2,4,16-triene (quantitative) as a pale-yellow, viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38].CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[O:10])[CH:3]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C)CCNC(=O)c1cc(Cl)ccn1
Temperature: 33 °C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
4-Chloropicolinic acid (0.50 g, 3.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.67 g, 3.5 mmol) and 1-hydroxybenzotriazole hydrate (0.53 g, 3.5 mmol) were dissolved in DMF (6 mL). N1,N1-dimethylethane-1,2-diamine (0.381 mL, 3.49 mmol) and DIEA (0.62 mL, 3.5 mmol) were added, and the reaction was stirred at 33° C. overnight. The solution was cooled, diluted with water and extracted with methylene chloride. The organic layer was dried and concentrated to give the crude 4-chloro-N-(2-(dimethylamino)ethyl)picolinamide (0.79 g).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.C1([O:23][C:24](=O)[NH:25][CH2:26][CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)C=CC=CC=1>O1CCOCC1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:9][C:24]([NH:25][CH2:26][CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)=[O:23])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Reactant: O=C(NCCc1c[nH]c2ccccc12)Oc1ccccc1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)NCCc2c[nH]c3ccccc23)CC1

Procedure:
4-Dimethylamino-4-phenyl-cyclohexylamine (more polar diastereomer) (218 mg, 1.0 mmole) was added to a solution of [2-(1H-indol-3-yl)ethyl]carbamic acid phenyl ester (280 mg, 1.0 mmole) in dioxane and refluxed for 12 h. Working up was performed by removing the dioxane by distillation and combining the residue with water. The batch was adjusted to pH 11 with 5M NaOH and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and evaporated. The product was obtained as a colorless oil in a yield of 404 mg (100%).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4]/[CH:5]=[CH:6]\[Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].BrC/C=C\[Sn](CCCC)(CCCC)CCCC.N1CC[C@@H]([O:44][C:45](=[O:47])[CH3:46])C1>>[CH2:8]([Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])/[CH:6]=[CH:5]\[CH2:4][N:3]1[CH2:1][CH2:2][C@@H:21]([O:47][C:45](=[O:44])[CH3:46])[CH2:20]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Reactant: CC(=O)O[C@@H]1CCNC1
Agent: CCCC[Sn](/C=C\CBr)(CCCC)CCCC
Product: CCCC[Sn](/C=C\CN1CC[C@@H](OC(C)=O)C1)(CCCC)CCCC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 3, starting from ((Z)-3-bromoprop-1-en-1-yl)-tributyl-stannane (Intermediate 2) and acetic acid (R)-pyrrolidin-3-yl ester.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]([CH3:37])[CH2:23][CH:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]([CH3:37])[CH2:23][CH:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)[CH2:17][CH2:16]1
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CC1CCNCC1)CC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
After a 4N hydrogen chloride in ethyl acetate (5 ml; 20 mmol) was added to a solution in methylene chloride (3 ml) of N,N-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]methylamine (640 mg; 1.5 mmol) synthesized by the above process under ice cooling. The ice bath was removed, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resultant crude crystals were recrystallized from methanol-diethyl ether, thereby obtaining 412 mg (yield: 82%) of the title compound as colorless needles (melting point: 280° C. or higher).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C@H:14]1[C@H: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)[CH2:15]1)=[O:13])=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C@H:14]1[C@H: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)[CH2:15]1)=[O:13])([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1NC(=O)[C@@H]1C[C@H]1c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1NC(=O)[C@@H]1C[C@H]1c1ccc2ccccc2c1

Procedure:
Prepared analogously to Example 2 from trans-3-(naphth-2-yl)-cyclopropanecarboxylic acid-N-(2-methoxycarbonyl-phenyl)-amide and sodium hydroxide solution in methanol.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br.O>C(O)(=O)C>[Br:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Cc1cccc(C(=O)O)c1O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Br)cc(C(=O)O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To a solution of 2-hydroxy-3-methyl-benzoic acid (10 g, 66.7 mmol, 1.0 eq) in acetic acid (100 mL) was added bromine (10.66 g, 66.7 mmol, 1.0 eq) slowly over 5 min. The mixture was stirred at room temperature for 24 h, then water was added slowly and the mixture was stirred for a further 30 min. The precipitate was collected by filtration and was washed with water and dried to give the title compound as a white solid (13.7 g, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([O:28][CH3:29])[CH:22]=2)=[N:8][CH2:7]1)=[O:5])[CH3:2]>[Pd].C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([O:28][CH3:29])[CH:22]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN=C(Cc2cc(C)cc(OC)c2)c2cc(OC)c(OC)cc21
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cnc(Cc2cc(C)cc(OC)c2)c2cc(OC)c(OC)cc12
Yield: 88.5 %

Procedure:
A solution of 6,7-dimethoxy-1-(3-methoxy-5-methyl-benzyl)-3,4-dihydro-isoquinoline-4-carboxylic acid ethyl ester (0.73 g, 1.8 mmol) and 10% palladium on carbon (230 mg) in xylene (15 mL) was refluxed overnight. The reaction mixture was cooled, filtered through celite, and concentrated in vacuo to afford 6,7-dimethoxy-1-(3-methoxy-5-methyl-benzyl)-isoquinoline-4-carboxylic acid ethyl ester as a light brown oil (0.63 g, 89%). This material was used without further purification: 1H NMR (300 MHz) compatible.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]2[CH:30]=[CH:29][N:28]3[N:31]=[CH:32][C:33]([CH:34]=[O:35])=[C:27]3[N:26]=2)[CH:3]=1.[BH4-].[Na+]>CO.[Cl-].[Na+].O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[C:4]([C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]2[CH:30]=[CH:29][N:28]3[N:31]=[CH:32][C:33]([CH2:34][OH:35])=[C:27]3[N:26]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C=O)c2n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(CO)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
A solution of (R)-tert-butyl 3-(4-fluoro-2-(1-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)propylcarbamate (85.0 mg, 0.176 mmol) in MeOH (2 mL) was first cooled to 0° C., then NaBH4 (4.04 mg, 0.176 mmol) was introduced, and the reaction was stirred at 0° C. for 1 hour. The reaction was diluted with brine and extracted with DCM in a phase separator cartridge. The combined organic extracts were concentrated to provide (R)-tert-butyl 3-(4-fluoro-2-(1-(3-(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)propylcarbamate (86 mg, 101% yield) as beige solid. MS (apci) m/z=468.1 (M+H−H2O).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH:21](NC(C)C)(C)C.IC>COCCOC.O.CN(C=O)C>[CH3:21][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)NCC/C=C/c1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CI
Product: CN(CC/C=C/c1cncnc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76.1 %

Procedure:
Under a nitrogen atmosphere, sodium hydride (0.78 g, 19.5 mmol, 60% dispersion in oil) was added to a stirring solution of IV (0.50 g, 2.0 mmol), 1,2-dimethyoxyethane (20 mL), DMF (25 mL), and a trace of diisopropylamine. The mixture was stirred at ambient temperature for 45 min, and a solution of iodomethane (2.59 g, 18.3 mmol) in 1,2-dimethoxyethane (5 mL) was added. The mixture was stirred at ambient temperature for 3 days, cooled, and water (25 mL) was added dropwise. The mixture was diluted with water (200 mL) and extracted with chloroform (7×50 mL). All chloroform extracts were combined, dried (Na2 SO4), filtered, and concentrated by rotary evaporation. The residue was dried under high vacuum at ambient temperature to give a red-brown oil. The oil was chromatographed on silica gel (50 g), eluting with ethyl acetate. Selected fractions were combined, concentrated by rotary evaporation, and dried under high vacuum at ambient temperature to give compound V as a light yellow oil (0.40 g, 76.1%).
Reaction SMILES: Cl[N:2]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][CH:8]=2)[S:3]1.[NH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1>>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH:12]1[NH:11][N:2]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][CH:8]=2)[S:3]1
Reactant: NC1Cc2ccccc2C1
Reactant: ClN1Nc2cncnc2S1
Product: c1ccc2c(c1)CC(NN1Nc3cncnc3S1)C2
Yield: 51.7 %

Procedure:
Using 2-chloro-1-thia-2,3,5,7-tetraazaindene (50 mg, 0.29 mmol) (see J. Org. Chem. 26, 4961 (1961), J. Chem. Soc. (C) 1856 (1967)) and 2-aminoindan (120 mg, 0.90 mmol), a similar procedure to Production Example 190 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (41 mg, 0.15 mmol) having the following physical properties: