Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=NC=CC=1)#C.C([Li])CCC.[S].[Li][S:16][C:17]#[C:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.[NH2:25][C:26]1[S:30][N:29]=[C:28]([C:31](=[N:62][O:63][CH2:64][CH3:65])[C:32]([NH:34][CH:35]2[C:60](=[O:61])[N:37]3[C:38]([C:44]([O:46][CH:47]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:45])=[C:39]([CH2:42]I)[CH2:40][S:41][C@H:36]23)=[O:33])[N:27]=1.Cl>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C.O.C(OCC)(=O)C>[NH2:25][C:26]1[S:30][N:29]=[C:28]([C:31](=[N:62][O:63][CH2:64][CH3:65])[C:32]([NH:34][CH:35]2[C:60](=[O:61])[N:37]3[C:38]([C:44]([O:46][CH:47]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[O:45])=[C:39]([CH2:42][S:16][C:17]#[C:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH2:40][S:41][C@H:36]23)=[O:33])[N:27]=1
Reactant: [Li]SC#Cc1cccnc1
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1nsc(N)n1
Agent: C#Cc1cccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC#Cc3cccnc3)CS[C@H]12)c1nsc(N)n1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-ethynylpyridine (258 mg) in a mixture of tetrahydrofuran (7 ml) and hexamethylphosphoric triamide (0.3 ml) was dropwise added n-butyllithium (1.55M in hexane) (1.3 ml) at -30° C. Sulfur (72 mg) was added to the reaction mixture at -25° C. at once. The mixture was stirred for 30 minutes under ice-cooling and then allowed to warm to 15° C. to give a solution containing 3-(2-lithiothioethynyl)pyridine. This solution was added to a solution of benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-iodomethyl-3-cephem-4-carboxylate (syn isomer) (1.4 g) in tetrahydrofuran (20 ml) at -50° C. The mixture was stirred for 40 minutes at -50° C. To the mixture was added 6N hydrochloric acid (1 ml) at -60° C. The mixture was warmed up to ambient temperature. To the mixture was added a mixture of ethyl acetate and water. The separated organic layer was dried over sodium sulfate, concentrated in vacuo, and the residue was triturated in diisopropyl ether to give a solid. The solid was subjected to column chromatography on silica gel (15 g) eluting with a mixture of ethyl acetate and n-hexane (1:1 (V/V), 4:1 (V/V)). The fractions containing the object compound were combined, concentrated in vacuo, and the residue was triturated in diethyl ether to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[2-(3-pyridyl)ethynylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (576 mg).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[N:14][CH:13]=1.Cl>>[CH2:1]([O:8][C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[N:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cncc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1cncc(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 1 mL of benzyl alcohol cooled in an ice bath was added 0.1 g of 60% sodium hydride oil dispersion. After 15 min., 0.1 g of 6-chloro-2-pyrazinoic acid was added. The mixture was stirred at room temperature for 1 h, then acidified with 2 mL of 1N HCl. The mixture was cooled in an ice bath and the white precipitate collected by filtration. Drying under vacuum gave 0.132 g of 6-benzyloxy-2-pyrazinoic acid: mp 160°-162° C.; 1H NMR (400 MHz, CDCl3) 9.00 (s, 1H), 8.56 (s, 1H), 7.49-7.36 (m, 5H), 5.46 (s, 2H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[N:13]1[C:17](=[O:18])[CH2:16][NH:15][C:14]1=[O:19].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:1]([N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:7]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[F:5])[C:14]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C1CNC(=O)N1c1cc(F)ccc1F
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(=O)N(c2cc(F)ccc2F)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (1.05 equivalent) in methylene chloride (50 mL) was added dropwise to a solution of 3-(2,5-difluorophenyl)imidazolidine-2,4-dione (50 mmol) in methylene chloride (150 mL) containing triethylamine (1.1 equivalent) and a catalytic amount of dimethylaminopyridine. The solution was allowed to stir overnight at room temperature, then was diluted with methylene chloride, and washed with 10% HCl, with water and with brine (saturated), dried (MgSO4), filtered and concentrated to give N-acetyl-3-(2,5-difluorophenyl)imidazolidine-2,4-dione.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=3)[CH:20]=[C:19]([CH3:29])[C:18]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:12][CH:11]=1)[CH:6]([CH3:8])[CH3:7])C.CS(OC(C)CC1C=CC=C(OC)C=1)(=O)=O>>[CH3:28][O:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[C:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([CH:9]=[C:5]([CH:6]([CH3:8])[CH3:7])[C:4]([OH:36])=[O:3])=[CH:15][CH:14]=1)=[C:18]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:19]([CH3:29])=[CH:20]2
Reactant: CCOC(=O)C(=Cc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1)C(C)C
Agent: COc1cccc(CC(C)OS(C)(=O)=O)c1
Product: COc1ccc2c(Oc3ccc(C=C(C(=O)O)C(C)C)cc3)c(-c3ccccc3)c(C)cc2c1

Procedure:
Similarly isomer (2) of 2-[4-(6-Methoxy-3-methyl-2-phenyl-naphthalen-1-yloxy)-benzylidene]-3-methyl-butyric acid ethyl ester (222-1) (0.191 g, 0.397 mmol) afforded 0.114 g (63%) of isomer (2) (223-2) of the title compound as solid. 1H NMR (400 MHz, d-CDCl3): δ 1.15 (d, J=7.0 Hz, 6H), 2.22 (s, 3H), 2.70-2.77 (m, 1H), 3.91 (s, 3H), 6.47-6.51 (m, 3H), 7.00-7.04 (m, 3H), 7.09-7.13 (m, 3H), 7.18-7.25 (m, 4H), 7.54 (s, 1H), 7.73 (d, J=9.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=4)=[O:22])=[CH:16][C:14]=3[CH:15]=2)=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.Cl.[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[O:7])=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)=[O:22])=[CH:16][C:14]=2[CH:15]=1
Reactant: COC(=O)CCCCCN
Reactant: Cc1cccc(NC(=O)Nc2ccc3sc(-c4cc(C(=O)O)cnc4N)cc3c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCNC(=O)c1cnc(N)c(-c2cc3cc(NC(=O)Nc4cccc(C)c4)ccc3s2)c1
Temperature: 50 °C

Procedure:
The reaction mixture of 6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinic acid (84 mg, 0.2 mmol, 1 eq), methyl 6-aminohexanoate hydrochloride (43.7 mg, 1.2 eq), DMAP (5 mg, 0.2 eq), and EDCI (46.1 mg, 1.2 eq) in anhydrous 1,2-dichloroethane (3 mL) was stirred and heated at 50° C. for 2 hours. It was then diluted with ethyl acetate, washed sequentially with aqueous NH4Cl, saturated aqueous NaHCO3, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the solid residue was triturated with EtOAc-Hex (3:1) yielding methyl 6-[({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}carbonyl)amino]hexanoate as a white solid in amount of 83 mg.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH:12]1[CH2:18][O:19][CH3:20])=O)C1C=CC=CC=1.I[C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1.Br>C(O)(=O)C>[NH2:28][C:23]1[C:22]2[C:23](=[CH:22][C:27]([CH2:26][N:14]3[CH2:15][CH2:16][NH:11][CH:12]([CH2:18][O:19][CH3:20])[C:13]3=[O:17])=[CH:26][CH:27]=2)[N:24]=[CH:25][N:24]=1
Reactant: Nc1ncccc1I
Reactant: COCC1C(=O)NCCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: COCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reaction time: 1 h

Procedure:
To a solution of 2-methoxymethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (5.8 g, 13.3 mmol) in 50 mL of acetic acid is added dropwise, 20 mL of a 30%HBr in AcOH solution. The solution is stirred for 1 hour. After this time, the solution is concentrated. The resulting crude product is purified by column chromatography eluting with CH2Cl2:MeOH:NH4OH (20:5:1). The title compound (2.0 g, 6.6 mmol) is obtained as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ8.60 (s, 1H), 7.72 (m, 2H), 7.48 (d, 1H), 5.60 (bs, 2H), 4.72 (AB, 2H), 3.87 (m, 2H), 3.71 (m, 1H), 3.42 (m, 1H), 3.40 (s, 3H), 3.19 (m, 2H), 3.02 (m, 1H). MS (ion spray) m/z 302, (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][CH2:27][CH3:28])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[NH2:30][OH:31]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][CH2:27][CH3:28])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=[N:30][OH:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCCCC(=O)CCCn1c(CCC)nc2c(N)nc3ccccc3c21
Reactant: NO
Agent: Cl
Product: CCCCCCC(CCCn1c(CCC)nc2c(N)nc3ccccc3c21)=NO

Procedure:
By the general method described in Part F of Example 30, 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one was reacted with hydroxylamine hydrochloride to provide 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one oxime in about a 1 to 1 mixture of E and Z isomers as a white solid after recrystallization from aqueous methanol, mp 113-115° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9](=O)[NH:8][N:7]=1.P(Cl)(Cl)([Cl:18])=O>ClC(Cl)C>[Cl:18][C:9]1[N:8]=[N:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[C:11]2[S:12][CH:13]=[CH:14][C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(-c2cccs2)c2sccc12
Solvent: CC(Cl)Cl
Product: Clc1nnc(-c2cccs2)c2sccc12
Temperature: 100 °C
Reaction time: 10 h
Yield: 95.8 %

Procedure:
0.30 g of 7-(2-thienyl)thieno[2,3-d]pyridazine-4(5H)-one and 0.30 g of phosphorus oxychloride were dissolved in 10 ml of dichloroethane, and the solution was stirred at 100° C. for 10 hours. The reaction solution was concentrated, and a 1-N aqueous KOH solution was added thereto under cooling with ice. The solution was extracted with chloroform and dried. The solvent was distilled off, thereby obtaining 0.31 g of 4-chloro-7-(2-thienyl)thieno-[2,3-d]pyridazine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:14]([O:16][Si:17]([C:20]([CH3:21])([CH3:23])[CH3:22])([CH3:18])[CH3:19])[CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 72 h
Yield: 100.3 %

Procedure:
A solution of (2S,3R)-methyl 2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)butanoate (614a) (1.07 g, 3.08 mmol) in THF (25 mL) was treated with 1.0 M aq. LiOH (6.16 mL, 6.16 mmol) and the mixture was stirred for 72 h. The mixture was diluted with saturated aq. brine (100 mL) containing 1.0 M aq. HCl (10 mL), and extracted into EtOAc (2×100 mL). The combined organic extracts were dried (MgSO4) and concentrated to give (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)butanoic acid (614b) (1.03 g, 3.09 mmol, 100% yield) as a viscous colorless oil that crystallized upon standing. LC-MS m/z 356.1, [M+Na]+.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]1[CH2:7][CH2:8][N:9]([CH3:12])[CH2:10][CH:11]=1.C([SnH](CCCC)CCCC)CCC>C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:12][N:9]1[CH2:8][CH2:7][C:6]2([C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5]2)[CH2:11][CH2:10]1
Reactant: CN1CC=C(COc2ccccc2I)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CN1CCC2(CC1)COc1ccccc12
Yield: 73 %

Procedure:
4-(2-Iodophenoxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (D2, 8.72 g, 0.026 mol) and AIBN (0.20 g, 0.0012 mol) were stirred at reflux under Ar in benzene (500 ml) as tributyltin hydride (14.3 ml, 0.053 mol) was added dropwise in benzene (100 ml) over 1 h. The mixture was stirred at reflux for a further 4.5 h, cooled and evaporated. The residue was dissolved in ethyl acetate, and extracted with dil. HCl. The extract was basified (sat. K2CO3 solution) and extracted with ethyl acetate. This organic extract was dried (Na2SO4) and evaporated to give a brown solid, which was chromatographed on silica gel, eluting with 0-8% methanol/chloroform (gradient) to give the title compound (3.86 g, 69%) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[N:3]=1.[O:25]=[C:26]1[N:30]([CH2:31][C:32]([OH:34])=[O:33])[C:29](=[O:35])[CH2:28][S:27]1>>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:28]3/[C:29](=[O:35])[N:30]([CH2:31][C:32]([OH:34])=[O:33])[C:26](=[O:25])[S:27]/3)[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:22])([F:23])[F:24])[N:3]=1
Reactant: O=C(O)CN1C(=O)CSC1=O
Reactant: O=Cc1ccc2c(c1)c(Br)nn2Cc1ccc(Cl)cc1C(F)(F)F
Product: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(c2)c(Br)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O

Procedure:
[(5Z)-5-({3-Bromo-1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid was prepared from 3-bromo-1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazole-5-carbaldehyde and (2,4-dioxothiazolidin-3-yl)acetic acid following General Procedure F.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(C)(C)C.[ClH:29]>>[ClH:29].[ClH:29].[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][CH2:21][NH:20][C:19](=[O:27])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7]
Reactant: CN(C)CCCNC(=O)CCCCCCCCCCCNC(=O)OC(C)(C)C
Agent: Cl
Product: CN(C)CCCNC(=O)CCCCCCCCCCCN
Temperature: 25 °C
Reaction time: 14 h

Procedure:
[11-(3-Dimethylaminopropylcarbamoyl)undecyl]carbamic acid tert-butyl ester (4) (0.087 g, 0.22 mmol) was treated with HCl (4 M in dioxane, 2 mL, 8 mmol) and the mixture stirred at room temperature for 14 hours. The reaction was then concentrated in vacuo and further dried under high vacuum. The resulting white solid (0.081 g, 99%) was used directly without further purification. m/z (ESI) 300 [C17H37N3O+H]+.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:33][CH3:34])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCOCC1>[CH2:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:17]1[O:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])[C:11]=2[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH3:34]
Reactant: CCc1ccccc1-c1oc2ncnc(NCCCCCC(=O)OC)c2c1-c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1ccccc1-c1oc2ncnc(NCCCCCC(=O)O)c2c1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 45 mg (0.10 mmol) 6-{[6-(2-ethylphenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester in 2.0 ml dioxan and add 0.5 ml 1 N sodium hydroxide solution. Stir for 16 h at RT, then add 0.5 ml 1 N hydrochloric acid and 5 ml ethyl acetate. Separate the organic phase, dry over sodium sulphate, filter and concentrate by evaporation. 38 mg (87% of theor.) of the target compound is obtained.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][C:9]1([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](C2CCCCO2)[N:16]=[C:15]3[C:27]2[N:32]=[C:31]([O:33][C@H:34]3[CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38][C:35]43[CH2:37][CH2:36]4)[CH:30]=[N:29][CH:28]=2)[CH2:11][CH2:10]1>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH2:37]1[C:35]2([CH2:38][CH2:39][NH:40][CH2:41][C@@H:34]2[O:33][C:31]2[N:32]=[C:27]([C:15]3[C:14]4[C:18](=[CH:19][CH:20]=[C:12]([C:9]5([CH3:8])[CH2:11][CH2:10]5)[CH:13]=4)[NH:17][N:16]=3)[CH:28]=[N:29][CH:30]=2)[CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5(C)CC5)cc34)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(c2ccc3[nH]nc(-c4cncc(O[C@H]5CNCCC56CC6)n4)c3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
TFA (1.7 mL, 22.07 mmol) was added to a solution of (4R)-tert-butyl 4-(6-(5-(1-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (96.3 mg, 0.172 mmol) in DCM (1.7 mL) and the resulting solution was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo and the residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% CH3CN/H2O+0.1% TFA, 15 min, 254 nm) to provide 3-(6-((4R)-6-azaspiro[2.5]oct-4-yloxy)-2-pyrazinyl)-5-(1-methylcyclopropyl)-1H-indazole 2,2,2-trifluoroacetate (64.6 mg, 0.132 mmol, 77% yield) as a yellow solid: 1H NMR (400 MHz, MeOH) δ ppm 9.02 (1 H, s), 8.26-8.33 (1H, m), 8.17-8.22 (1 H, m), 7.54 (1 H, d, J=8.8 Hz), 7.43 (1 H, dd, J=8.7, 1.5 Hz), 5.09 (1H, s), 3.90 (1 H, d, J=13.1 Hz), 3.60 (1 H, d, J=12.3 Hz), 3.47-3.55 (1 H, m), 3.33-3.39 (1 H, m), 2.65-2.77 (1 H, m), 1.49 (3 H, s), 1.23 (1 H, d, J=14.7 Hz), 1.01 (1 H, dt, J=9.7, 5.1 Hz), 0.90-0.95 (2 H, m), 0.82-0.90 (3 H, m), 0.75-0.81 (1 H, m), 0.64-0.73 (1 H, m). 19F NMR (377 MHz, MeOH) δ ppm −77.48 (3 F, s). MS (ESI, pos. ion) m/z: 376.3 (M+1).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[NH:23]1[CH2:28][CH2:27][S:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:7][CH:6]([N:23]3[CH2:28][CH2:27][S:26][CH2:25][CH2:24]3)[CH2:9]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C1CSCCN1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(C(c2ccccc2)N2CC(N3CCSCC3)C2)cc1
Yield: 91 %

Procedure:
A mixture of 1-(Diphenylmethyl)azetidin-3-yl methanesulfonate (see J. Org. Chem.; 56; 1991; 6729; 10 g, 31.5 mmol), thiomorpholine (3.9 g, 38 mmol) and DIPEA (4.9 g, 38 mmol) was refluxed overnight. The volatiles were removed by evaporation and the residue was partitioned between CH2Cl2 and NaHCO3 aq. The organic layer was washed twice with NaHCO3 aq. and then extracted with an aqueous solution of citric acid (3×70 mL of 1M). The aqueous layer was cooled and then pH adjusted with aqueous NaHCO3 and then 2M NaOH aq. The mixture was extracted with a mixture of CH2Cl2-EtOAc-ethanol and the organic solution was dried over MgSO4 and then removed by evaporation. There was obtained 9.3 g (91%) of 4-[1-(diphenylmethyl)azetidin-3-yl]thiomorpholine as a pale yellow solid. 1H NMR (400 MHz, CDCl3): 2.5 (m, 4H), 2.7 (m, 4H), 2.8 (t, 2H), 3.0 (qn 1H), 3.4 (m, 2H), 4.4 (s, 1H), 7.1-7.4 (m, 1OH); LCMS: m/z 325 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][Br:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Br)cc1CBr
Yield: 69.7 %

Procedure:
A mixture of 4-bromo-1-chloro-2-methylbenzene (5.0 g, 24.0 mmol), N-bromosuccinimide (4.4 g, 25.0 mmol), and benzoyl peroxide (700 mg, 2.9 mmol) in anhydrous carbon tetrachloride (85 mL) was stirred at reflux for 4 hours. Dichloromethane (50 mL) was added. The mixture was extracted with 1 N NaOH (1×150 mL) and brine (1×150 mL). The organic extract was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-5% EtOAc/hexanes), affording 4-bromo-2-(bromomethyl)-1-chlorobenzene (4.76 g, 70% yield). The product was used without further purification.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:38][CH3:39])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]1[N:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[NH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:38][CH3:39])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]1[N:13]=[CH:12][C:11]([N:76]2[CH2:81][CH2:80][O:79][CH2:78][CH2:77]2)=[CH:10][N:9]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)CCCCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoate (300 mg) is dissolved in toluene (5 ml) and thereto are added tris(dibenzylideneacetone)dipalladium (37 mg), 2-(di-tert-butylphosphino)biphenyl (48 mg), sodium tert-butoxide (58 mg), and morpholine (53 μl) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give ethyl 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoate (254 mg). MS (m/z): 764 [M+H]+