Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:18](Cl)(=[O:22])/[CH:19]=[CH:20]/[CH3:21]>C1COCC1>[C:18]([N:8]1[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])(=[O:22])/[CH:19]=[CH:20]/[CH3:21]
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: C/C=C/C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To a stirred solution of (4S)-4-phenyl-1,3-oxazolidin-2-one (12 g, 73.5 mmol) in THF (200 mL) was added n-BuLi (2.5 M, 29.4 mL, 73.5 mmol) dropwise via a syringe at −78° C. The resulting reaction mixture was stirred at −78° C. for 5 minutes before (2E)-but-2-enoyl chloride (8.46 mL, 88.0 mmol) was added dropwise via a syringe. The reaction mixture was allowed to warm to ambient temperature and was quenched by addition of brine (100 mL) and water (100 mL). A mixture of ethyl acetate and hexanes (1:2, 100 mL) was added to partition the mixture and the organics were separated, dried over sodium sulfate, filtered and concentrated. The resultant oil was recrystallized in 5% ethyl acetate in hexanes (after seeding with crystals obtained from earlier batches) to yield (4S)-3-[(2E)-but-2-enoyl]-4-phenyl-1,3-oxazolidin-2-one (15.7 g, 67.9 mmol). 1H NMR (500 MHz, CDCl3) δ7.4 (m, 6H), 5.5 (m, 1H) 4.73 (t, J=8.8 Hz, 1H), 4.30 (m, 1H), 1.97 (dd, J=6.8, 1.5 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[N+:16](/[CH:19]=[CH:12]/[C:11]1[CH:14]=[CH:15][C:8]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:9][CH:10]=1)([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Oc2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Oc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A mixture of 4-(pyridin-2-yloxy)-benzaldehyde (9.3 g, 47 mmol) described in Manufacturing Example 209-1-1, nitromethane (14 g, 230 mmol), ammonium acetate (11 g, 140 mmol), and acetic acid (50 mL) was stirred for 1 hour and 30 minutes at 100° C. This mixture was cooled to room temperature, and water was added to precipitate a solid. The solid was filtered to obtain the title compound (9.9 g, 87%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=2[C:24]([NH2:26])=[O:25])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:32][N:33]([CH2:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][C:43]([O:48][CH3:49])=[C:44]([NH2:47])[CH:45]=2)[CH2:40][CH2:39]1)=[O:37])[CH3:34].Cl.O1CCOCC1>FC(F)(F)CO.[NH4+].[OH-].C1COCC1>[CH3:32][N:33]([CH3:34])[CH2:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][C:43]([O:48][CH3:49])=[C:44]([NH:47][C:2]3[N:3]=[C:4]([NH:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=4[C:24]([NH2:26])=[O:25])[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=3)[CH:45]=2)[CH2:40][CH2:39]1)=[O:37]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Reactant: COc1cc2c(cc1N)N(C(=O)CN(C)C)CC2
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: OCC(F)(F)F
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
A mixture of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (11 g, 24 mmol), 1-[(dimethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (5 g, 20 mmol), a 4M HCl solution in dioxane (25 mL, 100 mmol) and 2,2,2-trifluoroethanol (250 mL) was heated at 80° C. for 16 h. The resulting mixture was allowed to cool to rt and diluted with a 27% aqueous NH4OH solution (250 mL) and THF (250 mL). The reaction mixture was stirred at rt overnight. The resulting slurry was filtered and the solids were triturated using H2O (300 mL), Et2O (300 mL) and finally EtOAc (300 mL). The solids were dissolved in THF, concentrated onto Celite and purified by silica gel chromatography using 0-10% MeOH (containing 0.2% NH3)/CH2Cl2. The solids obtained following chromatography were triturated using a mixture of MeOH and CH2Cl2to afford 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide as a beige solid (6.8 g, 51%).
Reaction SMILES: C1([SiH3])C=CC=CC=1.C([O:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:13]1=[O:36])C=C>ClCCl>[CH2:29]([N:14]1[C:15]2[C:20](=[CH:19][C:18]([F:23])=[C:17]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:16]=2)[C:21](=[O:22])[N:12]([OH:11])[C:13]1=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C=CCOn1c(=O)c2cc(F)c(N3CCCC3)cc2n(Cc2ccccc2)c1=O
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(Cc2ccccc2)c(=O)n1O
Reaction time: 17 h
Yield: 42.2 %

Procedure:
Phenylsilane (0.07 mL, 0.56 mmol) and palladium tetrakistriphenylphosphine (17 mg, 0.015 mmol) were added to a solution of 3-allyloxy-1-benzyl-6-fluoro-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example B-4, 0.15 g, 0.4 mmol) in 10 mL of dichloromethane at 0° C. The mixture was stirred for 17 hours and filtered to give 0.06 g of the title compound as a solid, mp 234-236° C.
Reaction SMILES: [Cl-].[CH2:2]([P+](CCCC)(CCCC)CCCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)C1C=CC=CC=1.[Cl:30][SiH:31]([Cl:33])[Cl:32]>>[CH2:2]([Si:31]([Cl:33])([Cl:32])[Cl:30])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: CCCC[P+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCc1ccccc1
Product: Cl[Si](Cl)(Cl)Cc1ccccc1
Yield: 802.5 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.26 g (0.79 mmol) of benzyltributylphosphonium chloride, 1.00 g (7.90 mmol) of benzyl chloride, and 3.21 g (23.7 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 1.43 g of benzyltrichlorosilane (yield; 80%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][C:11]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[O:10][CH:9]([CH2:25][O:26]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:8]1.[CH3:37][O-].[Na+]>>[CH3:37][O:26][CH2:25][CH:9]1[O:10][C:11]2([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:16][CH2:17]2)[CH2:12][N:7]([C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:8]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(c3ncccn3)CC3(CCN(C(=O)OC(C)(C)C)CC3)O2)cc1
Reactant: C[O-]
Agent: [Na+]
Product: COCC1CN(c2ncccn2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1

Procedure:
Tert-butyl 4-(pyrimidin-2-yl)-2-(tosyloxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (1.83 g, 3.53 mmol) was dissolved in a solution of sodium methoxide (71 mL of 0.5 M in methanol, 35 mmol) and refluxed for 18 h. The solvent was evaporated to dryness and the residue dissolved in dichloromethane (200 mL). The solution was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography (5-80% ethyl acetate/hexanes) provided tert-butyl 10-(methoxymethyl)-8-pyrimidin-2-yl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate as colorless oil. ESI-MS m/z calc. 378.2. found 379.3 (M+1)+; Retention time: 1.54 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 8.31 (d, J=4.8 Hz, 2H), 6.58 (t, J=4.8 Hz, 1H), 4.72-4.52 (m, 2H), 3.91 (ddd, J=10.9, 7.9, 4.9 Hz, 1H), 3.76-3.59 (m, 2H), 3.56-3.44 (m, 2H), 3.40 (s, 3H), 3.13 (t, J=11.1 Hz, 1H), 2.85-2.65 (m, 2H), 1.98 (d, J=14.6 Hz, 2H), 1.59 (dd, J=8.7, 4.5 Hz, 2H), 1.45 (s, 9H), 1.44-1.37 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>>[Br:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: OB(O)c1ccccc1Br
Product: Brc1cccc(-c2ccccn2)c1

Procedure:
2-bromophenylboronic acid (35.0 g, 0.174 mol) was reacted with 2-bromopyridine (55.1 g, 0.348 mol) under standard Suzuki coupling condition. The excess 2-bromopyridine was removed via vacuum distillation at 125° C. The product was collected at 180° C. as a light yellow liquid (29 g, 71%) and used for the next reaction without additional purification.
Reaction SMILES: [OH:1][C@H:2]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:3][N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)=[CH:16][CH:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+].[F:41][C:42]1[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=1[CH2:44]Br>C(#N)C>[F:41][C:42]1[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=1[CH2:44][N:24]1[CH:25]=[CH:26][N:27]=[C:23]1[CH2:22][C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][N:4]([CH2:3][C@H:2]([OH:1])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[CH:15][CH:16]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(NC(=O)Cc2ncc[nH]2)cc1)C[C@H](O)c1ccccc1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCc1ccc(NC(=O)Cc2nccn2Cc2ccccc2F)cc1)C[C@H](O)c1ccccc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 50.9 %

Procedure:
To a solution of 403 mg of tert-butyl (R)-N-(2-hydroxy-2-phenylethyl)-N-[2-[4-[(2-1H-imidazol-2-ylacetyl)amino]phenyl]ethyl]carbamate in 10 ml of acetonitrile were added 120 mg of potassium carbonate and 164 mg of 2-fluorobenzyl bromide successively at room temperature. The reaction solution was stirred at 50° C. for 12 hours. Insoluble matters were filtered off using Celite, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography to give 253 mg of tert-butyl (R)-N-[2-[4-[[2-[1-(2-fluorobenzyl)-1H-imidazol-2-yl]-acetyl]amino]phenyl]ethyl]-N-(2-hydroxy-2-phenylethyl)-carbamate.
Reaction SMILES: [Br:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1.C(N(CC)CC)C.[ClH:44].[CH3:45][N:46]([CH3:51])[CH2:47][C:48]([Cl:50])=[O:49].Cl>C(Cl)Cl>[ClH:50].[ClH:44].[Br:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:48](=[O:49])[CH2:47][N:46]([CH3:51])[CH3:45])[CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1
Reactant: COc1cccc(Sc2cnc(Nc3nc(C4CCNCC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(Sc2cnc(Nc3nc(C4CCN(C(=O)CN(C)C)CC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
A 20 mL vial was charged with 3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine (40 mg, 0.068 mmol), triethylamine (0.028 mL, 0.20 mmol), and CH2Cl2 (2 mL). 2-(Dimethylamino)acetyl chloride hydrochloride (12.9 mg, 0.0817 mmol) was added and stirred at room temperature for 10 minutes. The reaction was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (15% MeOH in EtOAc with 0.3% ammonia) to afford 1 the title compound (35.6 mg, 70.1% yield) after HCl salt formation. 1H NMR (d6-DMSO) δ 11.15 (bs, 1H), 9.60 (bs, 1H), 8.17 (d, 1H), 7.75 (m, 1H), 7.32 (m, 2H), 7.21 (t, 1H), 6.94 (d, 1H), 6.79 (m, 1H), 6.75 (s, 1H), 6.71 (m, 2H), 4.42 (d, 1H), 4.31 (qd, 2H), 3.69 (s, 3H), 3.19 (t, 1H), 2.93 (m, 1H), 2.82 (m, 6H), 2.04 (d, 2H), 1.64 (m, 1H), 1.52 (m, 1H). Mass spectrum (apci) m/z=674.3 (M+H-2HCl).
Reaction SMILES: Cl[CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1.[C-:15]#[N:16].[Na+]>CS(C)=O>[C:15]([CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1)#[N:16]
Reactant: [C-]#N
Reactant: COC(=O)c1cccc2c1CCC2Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc2c1CCC2C#N
Reaction time: 8 h

Procedure:
In 80 ml. of dimethylsulfoxide is dissolved 15 g. of methyl 1-chloroindan-4-carboxylate and the solution is stirred. Then, 5.3 g. of sodium cyanide is added, followed by stirring for 8 hours. Following the addition of 750 ml. of water, the reaction mixture is extracted with ether. The extract is washed with a saturated aqueous solution of sodium chloride and, then, dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (500 g. silica gel; eluant: chloroform). The described procedure gives methyl 1-cyanoindan-4-carboxylate as crystals melting at 76.5°-77.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1>[Pd].CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([C:12]([F:13])([F:14])[F:15])[CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 4-methoxy-1-nitro-2-trifluoromethyl-benzene (4.9 g, 22.2 mmol) and 5% palladium on carbon (210 mg) in EtOH (28 mL) is stirred for 2.5 h at RT, under a hydrogen atmosphere. The resulting suspension is filtered through a pad of celite. The filtrate is concentrated in vacuo to afford the title compound: ES-MS: 192.0 [M]+; single peak at tR=3.55 min (System 2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][NH:20][CH3:21].C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15](=[O:17])[N:20]([O:19][CH3:18])[CH3:21])[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Yield: 60.6 %

Procedure:
A solution of 4-[N-(tert-butoxycarbonyl)amino]-cyclohexane carboxylic acid (11.95 g, 49.0 mmol), O,N-dimethylhydroxylamine (4.88 g, 50.0 mmol), DCC (9.60 g, 50 mmol) and triethylamine (5.06 g, 50.0 mmol) in DMF (150 mL) was stirred at room temperature overnight. Water (500 mL) was added and the mixture was extracted with CHCl3. The organic phase was washed with water, dried and concentrated under reduced pressure. Purification by flash chromatography (hexane/EtOAc 1:1) gave [4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (8.50 g, 61%).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[F:12][C:13]1[CH:14]=[C:15]([C@@H:20]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])[CH:16]=[C:17]([F:19])[CH:18]=1>N1C=CC=CC=1>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:23][CH2:22][CH2:21][C@@H:20]([C:15]2[CH:16]=[C:17]([F:19])[CH:18]=[C:13]([F:12])[CH:14]=2)[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)c1ccc([C@@H](CCO)c2cc(F)cc(F)c2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC[C@H](c2ccc(S(C)(=O)=O)cc2)c2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Tosyl chloride (3 g) was added portionwise to pyridine (50 ml) at 5° C., followed by a solution of (3R)-3-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]propan-1-ol (3.1 g) in pyridine (15 ml) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured onto ice/2N HCl and extracted with diethyl ether (×2). The organic extracts were dried and evaporated to dryness to give (3R)-3-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]propyl 4-methylbenzenesulfonate as a solid. Yield 2.9 g. NMR (CDCl3): 2.4 (m, 2H), 2.5 (s, 3H), 3.05 (s, 3H), 3.95 (m, 2H), 4.2 (t, 1H), 6.7 9 m, 3H), 7.3 9 m, 4H), 7.75 (d, 2H), 7.85 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[CH2:6]1)=[O:4].[CH:21](NC(C)C)(C)C.[Li].IC>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:21])[CH2:9][CH2:8][N:7]([CH2:10][CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCN(CC2COc3ccccc3O2)C1
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCN(CC2COc3ccccc3O2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution containing 80 mg (0.29 mmol) of 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-pyrrolidine-3-carboxylic acid methyl ester in dry tetrahydrofuran (4.5 mL) at −78° C. under nitrogen was added 0.3 mL (0.58 mmol) of lithium diisopropylamine (2.0 M solution in heptane/tetrahydrofuran/ethylbenzene). The reaction mixture was stirred at −78° C. for 1 h and subsequently 0.04 mL (0.58 mmol) of iodomethane was added. The reaction mixture was allowed to warm to room temperature and the stirring was continued for 3 h. The reaction was quenched with 15 mL of saturated aqueous NH4Cl-solution and the tetrahydrofuran was evaporated off under vacuum. Water (50 mL) was added and the pH was adjusted to 10 using 1M Na2CO3. The water phase was extracted with ethyl acetate (3×25 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness, and the residue was dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[C:10]([C:31]#[N:32])=[N:11][C:12]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH:28]([CH3:30])[CH3:29])[N:22]=3)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:5][CH:4]=1.[OH-:44].[Na+]>O1CCOCC1>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:43][CH:42]=2)[C:9]2[C:10]([C:31]([NH2:32])=[O:44])=[N:11][C:12]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH:28]([CH3:30])[CH3:29])[N:22]=3)=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:14]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(-c3ccccc3)c(-c3ccc(=O)n(C(C)C)n3)nc2C#N)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(-c3ccccc3)c(-c3ccc(=O)n(C(C)C)n3)nc2C(N)=O)cc1

Procedure:
A suspension of 3-[bis(4-methoxybenzyl)amino]-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbonitrile (3.00 g) in a mixture of 2N aq. NaOH (30 ml) and dioxane (21 ml) was refluxed for 36 hours. After cooling, the mixture was extracted with EtOAc, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (20:80 v/v) to give a solid. The solid was crystallized from a mixture of n-hexane and acetone to give 3-[bis(4-methoxybenzyl)amino]-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarboxamide (2.56 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16](=[O:26])[NH:17][CH2:18][C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH:13]=[C:12]([C:27](O)=[O:28])[CH:11]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[OH:63][CH:64]1[CH2:67][NH:66][CH2:65]1>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([C:27]([N:66]2[CH2:67][CH:64]([OH:63])[CH2:65]2)=[O:28])[CH:13]=[C:14]([C:16]([NH:17][CH2:18][C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:26])[CH:15]=1)#[N:2]
Reactant: OC1CNC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)c(C#N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CC(O)C3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round-bottom flask was charged with 2′-cyano-4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (80 mg, 0.24 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (80 mg, 0.42 mmol), 1-hydroxybenzotriazole hydrate (64 mg, 0.42 mmol), N,N-diisopropylethylamine (110 mg, 0.83 mmol), methylene chloride (5 mL) and 3-hydroxyazetidine hydrochloride (45 mg, 0.42 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified via flash chromatography to afford the desired product as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:8]2)=[CH:2]1.C[O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35]Cl>>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:35][CH2:34][O:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([OH:37])=[O:25])[CH2:20][CH2:19]3)=[CH:8]2)=[CH:2]1
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccoc1
Reactant: COC(=O)c1ccccc1OCCCl
Product: COc1ccc2c(c1)c(C1CCN(CCOc3ccccc3C(=O)O)CC1)cn2Cc1ccoc1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 3.7 g (11.9 mmol) of 1-furan-3-ylmethyl-5-methoxy-3-piperidin-4-yl-1H-indole and 3 g (13.9 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After standard work-up, 3.2 g (57% of yield) of the expected acid were obtained.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH2:33][O:34][CH2:35][CH3:36])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][NH:38][CH2:39][CH2:40][C:41]([O:43]CC)=[O:42].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)[O:20][C:19]=2[CH2:33][O:34][CH2:35][CH3:36])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:38]([CH3:37])[CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: CCOCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
A solution of 4-(cyclohexyl{2-(ethoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methoxy)benzoic acid (141 mg), ethyl 3-(methylamino)propanoate (45 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (65 mg), hydroxybenzotriazole monohydrate (52 mg) and triethylamine (47 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.5 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (93 mg, 81%).